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Objective: To evaluate the accuracy of pulsed Doppler-derived fetal PR interval measurements obtained by physicians participating in a multicenter prospective fetal echocardiographic study. Methods: Echocardiograms on healthy fetuses were performed and evaluated by 15 pediatric cardiologists/perinatologists across the United States who are participating in a larger clinical trial involving fetuses at risk for autoantibody-associated congenital heart block. Prior to enrolling women in the main trial, each physician was provided with a teaching tape to demonstrate how the pulsed Doppler-derived PR interval is measured. The procedure involves placing a gated pulsed Doppler sample volume in the left ventricle at the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract in an apical 5-chamber view, and simultaneously obtaining left ventricular filling and emptying. Time intervals are measured from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole). This represents the mechanical PR interval. Each physician measured the pulsed Doppler-derived fetal PR interval on 5 different subjects recruited from the physician’s specific site. To validate each physician’s technique, the tapes were sent to a central facility and the same intervals were remeasured by an experienced central reader (D.M.F.). A physician was determined to have adequate ability to measure the fetal PR interval if all 5 measurements were within ± 30 ms of the central reader’s measurements, where 30 ms corresponds to 25% of the mean observed in normative PR interval data. This difference was deemed to be the minimum clinically important difference in Doppler PR interval. Results: Fourteen of the 15 physicians were considered to have adequate ability to measure the fetal PR interval according to our established criterion. The overall mean difference between the physicians and the central reader’s measurements was –0.26 ± 11.04 ms (p = 0.84). In addition, 95% of the observed differences were included in the interval (–22.23 to 21.81), which is well within our clinically acceptable range of ± 30 ms. Conclusions: The pulsed Doppler assessment of the mechanical PR interval in the fetus can be accurately performed after minimal training. This technique may be a valuable tool for identification of early and potentially reversible conduction abnormalities in fetuses at risk for more advanced and permanent forms of heart block associated with maternal antibodies to SSA/Ro-SSB/La.Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as nonspecific "scar reaction." This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN., Methods: Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 ml/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex)., Results: IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogenous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/2 (0%), 1/3 (33%), 3/4 (75%), and 7/9 (78%) for i-IFTA grades 0, 1, 2, and 3, respectively (p = 0.028). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes., Conclusion: I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target., Lay Summary: Scar tissue often contains immune cells, but we still do not fully understand their role. In lupus nephritis (LN), this is typically dismissed as "nonspecific inflammation". However, our study analyzed kidney biopsies from 124 people with LN and found that inflammation in scarred areas may predict future kidney function loss. Specifically, we identified a type of immune cell, CD163+ macrophages, that may contribute to scarring and kidney damage. Our findings suggest that routinely assessing inflammation in scarred areas could help predict kidney health in LN patients and highlight a possible new target for therapies to prevent kidney damage.

Objective: Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response., Methods: Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead-based assays (Bio-Rad Bioplex 2200) and anti-C1q by enzyme-linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months., Results: Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti-C1q, anti-chromatin, anti-double-stranded DNA (dsDNA), and anti-ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti-C1q and-dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti-C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti-La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response., Conclusion: Baseline levels of anti-C1q and anti-dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti-C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Glucagon-like peptide-1 receptor agonists (GLP1-RA) are an emerging class of medications with demonstrated promise in improving cardiometabolic outcomes. Whether these drugs may be useful in mitigating the cardiac risk associated with SLE remains unknown, and a recent case of drug induced lupus secondary to GLP1-RA use calls the safety of GLP1-RAs in SLE patients into question. Accordingly, this retrospective analysis was initiated to evaluate outcomes of GLP1-RAs in SLE., Methods: All patients in the NYU Lupus Cohort who had used a GLP1-RA were eligible for inclusion. Patient characteristics were assessed at baseline (most recent rheumatology visit prior to starting GLP1-RA), 1-4 months, and 6-10 months after GLP1-RA initiation., Results: Of the 1211 patients in the cohort, only 24 had received a GLP1-RA. Six were excluded due to insufficient documentation regarding duration of medication use. Of the remaining 18 (median age 50), 17 (94%) were female and 9 (50%) were white. There was one mild-to-moderate flare at 6-10 months, but no patients accumulated new SLE criteria during the follow up period. Compared with baseline, median BMI was reduced by 3% at 1-4 months (p= 0.002) and 13% at 6-10 months (p= 0.001). Nine (50%) patients were initially denied insurance coverage for a GLP1-RA., Conclusion: While limited by a small sample size, this descriptive study showed that GLP1-RAs did not trigger flares above expected background rates and were associated with significantly decreased BMI. Future studies exploring the potential benefits of GLP1-RAs in patients with SLE are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort., Methods: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up., Results: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1)., Conclusion: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis., Competing Interests: Competing interests: MYC has received consulting fees from AstraZeneca, GlaxoSmithKline, Werfen, Mallinckrodt Pharmaceuticals, Celltrion, Organon, and MitogenDx (less than $10 000). AEC has received consulting fees from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Roche and Otsuka (less than $10 000 each) and a research grant from GlaxoSmithKline. CG has received consulting fees, speaking fees and/or honoraria from AstraZeneca, AbbVie, Amgen, UCB, GlaxoSmithKline, Merck Serono and BMS (less than $10 000 each) and grants from UCB. Grants from UCB were given not to CG but to Sandwell and West Birmingham Hospitals NHS Trust. DDG received consulting fees, speaking fees and/or honoraria from GlaxoSmithKline (less than $10 000). INB has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono and MedImmune (less than $10 000 each), and grants from UCB, Genzyme, Sanofi and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lehrman Group. KCK has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol Myers Squibb, Pfizer and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol Myers Squibb and Anthera (less than $10 000 each). MJF is Director of Mitogen Diagnostics Corporation (Calgary, Alberta, Canada) and a consultant to Werfen International (Barcelona, Spain), Grifols (Barcelona, Spain), Janssen Pharmaceuticals of Johnson & Johnson and Alexion Canada (less than $10 000 each)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Given fibromyalgia (FM) frequently co-occurs with autoimmune disease, this study was initiated to objectively evaluate FM in a multiracial/ethnic cohort of patients with systemic lupus erythematosus (SLE)., Methods: Patients with SLE were screened for FM using the 2016 FM classification criteria during an in-person rheumatologist visit. We evaluated hybrid Safety of Estrogens in Lupus National Assessment (SELENA)-SLE Disease Activity Index (SLEDAI) scores, SLE classification criteria, and Systemic Lupus International Collaborating Clinics damage index. We compared patients with and without FM and if differences were present, compared patients with FM with patients with non-FM related chronic pain., Results: 316 patients with SLE completed the FM questionnaire. 55 (17.4%) met criteria for FM. The racial composition of patients with FM differed from those without FM (P = 0.023), driven by fewer Asian patients having FM. There was no difference in SLE disease duration, SELENA-SLEDAI score, or active serologies. There was more active arthritis in the FM group (16.4%) versus the non-FM group (1.9%) (P < 0.001). The Widespread Pain Index and Symptom Severity Score did not correlate with degree of SLE activity (r = -0.016; 0.107) among patients with FM or non-FM chronic pain (r = 0.009; -0.024). Regarding criteria, patients with FM had less nephritis and more malar rash. Systemic Lupus International Collaborating Clinics damage index did not differ between groups., Conclusion: Except for arthritis, patients with SLE with FM are not otherwise clinically or serologically distinguishable from those without FM, and Widespread Pain Index and Symptom Severity Score indices do not correlate with SLEDAI. These observations support the importance of further understanding the underlying biology of FM in SLE., (© 2024 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes., Methods: A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores., Results: Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by > 0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains., Conclusion: Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis., Methods: Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day., Results: Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (OR adj  = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (OR adj  = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (OR adj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (OR adj  = 2.61 [95%CI = 0.93-7.33]; p = 0.069)., Conclusions: CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response., (© 2024. The Author(s).)

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

Objective: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up., Methods: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models., Results: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244-566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80-6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05-3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43-20.39)., Conclusion: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Competing Interests: The idea for this collaborative global response was born at the inaugural meeting of the EULAR study group for Reproductive Health and Family Planning in Milan in June, 2023. We would like to thank Kirsten Frøhlich (Danish Centre for Expertise in Rheumatology (CeViG), Danish Hospital for Rheumatic Diseases, Sonderborg, Denmark) for her immense logistic support throughout the process of this work. CN-P reports consultancy fees from Sanofi Aventis and UCB; speakers fees from UCB, Sanofi and Otsuka; is a medical advisor (medical advisory board) for the pregnancy sickness support charity; and a patron of the Lauren Page Trust. RJEMD reports grants from Galapagos and UCB; speakers fees from Galapagos, Eli Lilly, Novartis, and UCB; support for attending meetings from UCB; and participation on advisory boards for Galapagos and UCB. MM reports consulting fees from GSK, Eli Lilly, and AstraZeneca; speaker fees from UCB, Eli Lilly, AstraZeneca, GSK, Janssen, and AbbVie; participation on an advisory board for Idorsia; and has received Anifrolumab from AstraZeneca for compassionate use. RF-B reports consulting fees from AbbVie, Otsuka, and UCB; and speakers fees from Biogen, Bristol Myers Squibb, GSK, MSD, Novartis, Sanofi, and UCB. AM reports consulting fees from AbbVie, Biogen, Bristol Myers Squibb, MSD, Novartis, Janssen, Eli Lilly, Pfizer, Amgen, UCB, Gilead, Galapagos; speakers fees from AbbVie, Biogen, Bristol Myers Squibb, MSD, Novartis, Janssen, Eli Lilly, Pfizer, Amgen, UCB, Gilead, Galapagos; and support for attending meetings from AbbVie, Novartis, Galapagos, UCB, Janssen. AT reports speakers fees from GSK and UCB, and participation on advisory boards for Galapagos and UCB. BLB reports royalties from Up To Date and is a member of the data safety monitoring committee for the Stop Bloq study. MEBC reports grants from GSK and UCB and consulting fees from UCB. CC reports research support form Amgen, AstraZeneca, GSK, Janssen, Pfizer, Regeneron, Hoffman La-Roche-Genentech, Genzyme Sanofi-Aventis, Takeda Pharmaceutical Company, Sanofi, UCB, Leo Pharma, Sun Pharma Global FZE, Gilead, Novartis, and the Gerber Foundation; and Speaker honorarium from the American Academy of Allergy, Asthma & Immunology aunual meeting. JB reports consultancy fees from Related Sciences, GSK, and Bristol Myers Squibb. DA reports speakers fees from Bristol Myers Squibb. LA reports consulting fees from Sanofi. GB reports grants from AstraZeneca and Pfizer; consulting fees from AstraZeneca and Eli Lilly; and speakers fees from Aenorasis, AstraZeneca, GSK, Eli Lilly, Novartis, and SOBI. WB reports grants from UCB; is an advisory board member for UCB; payment for expert testimony; and is a member of data safety monitoring boards for the Lutein and Zeaxanthin in Pregnancy study and the Stop Bloq study. AB reports research grants from SOBI and participation on an advisory board for SOBI. IB reports consulting fees from AstraZeneca; speakers fees from Amgen, AstraZeneca, GSK, Eli Lilly, MSD, Roche, Sanofi Genzyme, and UCB; support for attending meetings from UCB; and is an advisory group member for AstraZeneca. RC reports speakers fees from GSK, AstraZeneca, Celgene, Janssen, Eli Lilly, Pfizer, UCB, Rubió, and Werfen. SAE reports support for attending meetings from Pfizer. GE reports consulting fees from GSK and Otsuka; and speakers fees from GSK, Otsuka, and Boehringer Ingelheim. JF reports speakers fees and support for attending meetings from UCB. RF-S reports consultancy fees, speakers fees, and support for attending meetings from AstraZeneca. BG reports grants from Bristol Myers Squibb, Pfizer, and Sandoz. IG reports speakers’ fees from Otsuka and participation on an advisory board for Novartis. MH reports research grants from AbbVie, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen Biologics BV, Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, and Nordforsk; speakers fees from Pfizer, Medac, and Sandoz; and participation on an advisory board for AbbVie. MH has chaired the steering committee of the Danish Rheumatology Quality Registry, which receives public funding from the hospital owners and funding from pharmaceutical companies. MH cochairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylorthritis on the basis of secondary data and is partly funded by Novartis. MK is an employee of GSK. RL is an employee of GSK. LFP-G reports consulting fees from Galapagos. MR is a member of the data safety monitoring committee for the Comparison of Step-up and step-down therapeutic strategies in childhood ArthritiS, which is partly supported by Pfizer. AS reports speakers fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, MSD, Eli Lilly, Pfizer, Roche, and UCB; and is principle investigator of the German Biologics Register RABBIT, which is supported by grants from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Galapagos, Hexal, Eli Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, Viatris Sante, UCB, and previously Roche. JV reports speakers’ fees from Eli Lilly, Novartis, Sandoz, and AbbVie. All other authors declare no competing interests.

Objective: Platelets are mediators of inflammation with immune effector cell properties and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet-associated lectin, galactoside-binding, soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE and as a potential biomarker associated with clinical phenotypes., Methods: We performed RNA sequencing on platelets from patients with SLE (n = 54) and on platelets from age-, sex-, and race/ethnicity-matched healthy controls (n = 18) and measured LGALS3BP levels in platelet releasate and in circulating serum. We investigated the association between LGALS3BP levels and the prevalence, disease severity, and clinical phenotypes of SLE and studied platelet-mediated effects on myeloid inflammation., Results: Platelets from patients with SLE exhibited increased expression of LGALS3BP (fold change 4.0, adjusted P = 6.02 × 10 -11 ). Platelet-released LGALS3BP levels were highly correlated with circulating LGALS3BP (R = 0.69, P < 0.0001), and circulating LGALS3BP levels were correlated with the severity of disease according to the SLE Disease Activity Index (r = 0.32, P = 0.0006). Specifically, circulating LGALS3BP levels were higher in SLE patients with lupus nephritis than in patients with inactive disease (4.0 μg/ml versus 2.3 μg/ml; P < 0.001). Interferon-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced proinflammatory cytokine production by macrophages., Conclusions: Our results support that platelets act as potent effector cells that contribute to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity., (© 2022 American College of Rheumatology.)

Background: Fibrosis and dystrophic calcification disrupting conduction tissue architecture are histopathological lesions characterizing cardiac manifestations of neonatal lupus (cardiac-NL) associated with maternal anti-SSA/Ro antibodies., Objectives: Increased appreciation of heterogeneity in fibroblasts encourages re-examination of existing models with the consideration of multiple fibroblast subtypes (and their unique functional differences) in mind. This study addressed fibroblast heterogeneity by examining expression of α-Smooth Muscle Actin (myofibroblasts) and of S100 Calcium-Binding Protein A4 (S100A4)., Methods: Using a previously established model of rheumatic scarring/fibrosis in vitro , supported by the evaluation of cord blood from cardiac-NL neonates and their healthy (anti-SSA/Ro-exposed) counterparts, and autopsy tissue from fetuses dying with cardiac-NL, the current study was initiated to more clearly define and distinguish the S100A4-positive fibroblast in the fetal cardiac environment., Results: S100A4 immunostaining was observed in 4 cardiac-NL hearts with positional identity in the conduction system at regions of dystrophic calcification but not fibrotic zones, the latter containing only myofibroblasts. In vitro , fibroblasts cultured with supernatants of macrophages transfected with hY3 (noncoding ssRNA) differentiated into myofibroblasts or S100A4 + fibroblasts. Myofibroblasts expressed collagen while S100A4 + fibroblasts expressed pro-angiogenic cytokines and proteases that degrade collagen. Cord blood levels of S100A4 in anti-SSA/Ro-exposed neonates tracked disease severity and, in discordant twins, distinguished affected from unaffected., Conclusions: These findings position the S100A4 + fibroblast alongside the canonical myofibroblast in the pathogenesis of cardiac-NL. Neonatal S100A4 levels support a novel biomarker of poor prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Firl, Halushka, Fraser, Masson, Cuneo, Saxena, Clancy and Buyon.)

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., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background:  Monocyte-platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet-platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain., Objectives:  To analyze the effect of platelets on monocyte activation and APT on MPA and platelet-induced monocyte activation., Methods:  Agonist-stimulated whole blood was incubated in the presence of P-selectin, PSGL1, PAR1, P2Y 12 , GP IIb/IIIa, and COX-1 inhibitors and assessed for platelet and monocyte activity via flow cytometry. RNA-Seq of monocytes incubated with platelets was used to identify platelet-induced monocyte transcripts and was validated by RT-qPCR in monocyte-PR co-incubation ± APT., Results:  Consistent with a proinflammatory platelet effector role, MPAs were increased in patients with COVID-19. RNA-Seq revealed a thromboinflammatory monocyte transcriptome upon incubation with platelets. Monocytes aggregated to platelets expressed higher CD40 and tissue factor than monocytes without platelets ( p  < 0.05 for each). Inhibition with P-selectin (85% reduction) and PSGL1 (87% reduction) led to a robust decrease in MPA. P2Y 12 and PAR1 inhibition lowered MPA formation (30 and 21% reduction, p  < 0.05, respectively) and decreased monocyte CD40 and TF expression, while GP IIb/IIIa and COX1 inhibition had no effect. Pretreatment of platelets with P2Y 12 inhibitors reduced the expression of platelet-mediated monocyte transcription of proinflammatory SOCS3 and OSM. CONCLUSIONS:  Platelets skew monocytes toward a proinflammatory phenotype. Among traditional APTs, P2Y 12 inhibition attenuates platelet-induced monocyte activation., Competing Interests: Dr. J.B. is PI for the NIH-funded ACTIV4a trial investigating P2Y12 inhibitors in patients hospitalized with COVID-19. C.C.R., M.A.S., T.T.W., M.C., K.M., T.S., H.B., and T.J.B. declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background and Objectives: Lupus nephritis remains a common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current guidelines recommend performing a kidney biopsy at a urine protein-creatinine ratio of ≥0.5 g/g. However, cross-sectional studies reported a high prevalence of active histologic lupus nephritis lesions, and even chronic irreversible scarring, in patients with low-grade proteinuria. This study was initiated to assess disease progression in patients with SLE and low-grade proteinuria to identify risk factors for progression to overt proteinuria suggestive of clinical lupus nephritis., Design, Setting, Participants, & Measurements: Patients with SLE who had an incident urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g without known lupus nephritis were identified from the Einstein Rheumatic Disease Registry. Patients who developed a random urinary protein-creatinine ratio of ≥0.5 g/g with or without biopsy during the follow-up period were defined as "progressors." Patients who progressed to a urinary protein-creatinine ratio of ≥0.5 g/g within 2 years of developing a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g were defined as "fast progressors," a subgroup expected to benefit most from early biopsies and therapeutic interventions., Results: Among 151 eligible patients with SLE and low-grade proteinuria at study entry, 76 (50%) progressed to a urinary protein-creatinine ratio of ≥0.5 g/g, of which 44 underwent a clinically indicated biopsy. The median (interquartile range) time from a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g to progression was 1.2 (0.3-3.0) years. Of the 20 biopsies performed in the first 2 years, 16 specimens showed active, treatable lupus nephritis. Low complement and shorter SLE duration at low-grade proteinuria onset were associated with progression to overt proteinuria across different analyses. Other associated factors included hypertension, diabetes mellitus, younger age, and the presence of hematuria., Conclusions: In this longitudinal cohort of patients with SLE and low-grade proteinuria at study entry, over half progressed to a urinary protein-creatinine ratio of ≥0.5 g/g in a short time period., (Copyright © 2022 by the American Society of Nephrology.)

Objective: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment., Methods: We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients., Results: Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury., Conclusion: Urine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker., (© 2021 American College of Rheumatology.)

Objective: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence., Methods: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded., Results: We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis., Conclusions: We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms., Competing Interests: Competing interests: JB and RFvV are Editors-in-Chief of Lupus Science & Medicine., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations., (© 2021 Gomes et al.)

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling., Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model., Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0., Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies., (© 2020, American College of Rheumatology.)

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology, which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed in order to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by IFN-γ. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, we observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8+ T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8+ cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways could be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Emerging urinary biomarkers continue to show promise in evaluating lupus nephritis (LN). Here, we screen urine from active LN patients for 1129 proteins using an aptamer-based platform, followed by ELISA validation in two independent cohorts comprised of 127 inactive lupus, 107 active LN, 67 active non-renal lupus patients and 74 healthy controls, of three different ethnicities. Urine proteins that best distinguish active LN from inactive disease are ALCAM, PF-4, properdin, and VCAM-1 among African-Americans, sE-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians. Most of these correlate significantly with disease activity indices in the respective ethnic groups, and surpass conventional metrics in identifying active LN, with better sensitivity, and negative/positive predictive values. Several elevated urinary molecules are also expressed within the kidneys in LN, based on single-cell RNAseq analysis. Longitudinal studies are warranted to assess the utility of these biomarkers in tracking lupus nephritis.

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.)

Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

The Accelerating Medicines Partnership (AMP) Lupus Network was established as a partnership between the National Institutes of Health, pharmaceutical companies, nonprofit stakeholders, and lupus investigators across multiple academic centers to apply high-throughput technologies to the analysis of renal tissue, urine, and blood from patients with lupus nephritis (LN). The AMP network provides publicly accessible data to the community with the goal of generating new scientific hypotheses and improving diagnostic and therapeutic tools so as to improve disease outcomes. We present here a description of the structure of the AMP Lupus Network and a summary of the preliminary results from the phase 1 studies. The successful completion of phase 1 sets the stage for analysis of a large cohort of LN samples in phase 2 and provides a model for establishing similar discovery cohorts., (© 2019, American College of Rheumatology.)

Objectives: In this study we aimed to investigate foetal and maternal pregnancy outcomes from a large multicentre cohort of women diagnosed with MCTD and anti-U1RNP antibodies., Methods: This multicentre retrospective cohort study describes the outcomes of 203 pregnancies in 94 consecutive women ever pregnant who fulfilled the established criteria for MCTD with confirmed U1RNP positivity., Results: The foetal outcomes in 203 pregnancies were as follows: 146 (71.9%) live births, 38 (18.7%) miscarriages (first trimester pregnancy loss of <12 weeks gestation), 18 (8.9%) stillbirths (pregnancy loss after 20 weeks gestation) and 11 (5.4%) cases with intrauterine growth restriction. Maternal pregnancy outcomes were as follows: 8 (3.9%) developed pre-eclampsia, 2 (0.9%) developed eclampsia, 31 (15.3%) developed gestational hypertension and 3 (1.5%) developed gestational diabetes. Women with MCTD and aPL and pulmonary or muscular involvement had worse foetal outcomes compared with those without. Moreover, we report a case of complete congenital heart block (0.45%) and a case of cutaneous neonatal lupus, both born to a mother with positive isolated anti-U1RNP and negative anti-Ro/SSA antibodies., Conclusion: In our multicentre cohort, women with MCTD had a live birth rate of 72%. While the true frequency of heart block associated with anti-U1RNP remains to be determined, this study might raise the consideration of echocardiographic surveillance in this setting. Pregnancy counselling should be considered in women with MCTD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Epidemiological data for primary discoid lupus erythematosus (pDLE) remain limited, particularly for racial/ethnic populations in the USA. The Manhattan Lupus Surveillance Program (MLSP) is a population-based retrospective registry of cases with SLE and related diseases including pDLE in Manhattan and was used to provide estimates of the prevalence and incidence of pDLE across major racial/ethnic populations., Methods: MLSP cases were identified from rheumatologists, hospitals and population databases. Two case definitions were used for pDLE: the primary case definition which was any physician diagnosis found in the chart and a secondary case definition which was limited to cases diagnosed by a rheumatologist and/or dermatologist. Rates among Manhattan residents were age-adjusted, and capture-recapture analyses were conducted to assess case under-ascertainment., Results: Based on the primary definition, age-adjusted overall prevalence and incidence rates of pDLE among Manhattan residents were 6.5 and 0.8 per 100 000 person-years, which increased to 9.0 and 1.3 after capture-recapture adjustment. Prevalence and incidence rates were approximately two and six times higher, respectively, among women compared with men (p<0.0001). Higher prevalence was also found among non-Latino blacks (23.5) and Latinos (8.2) compared with non-Latino whites (1.8) and non-Latino Asians (0.6) (p<0.0001). Incidence was highest among non-Latino blacks (2.4) compared with all other racial/ethnic groups. Similar relationships were observed for the secondary case definition., Conclusion: Data from the MLSP provide epidemiological estimates for pDLE among the major racial/ethnic populations in the USA and reveal disparities in pDLE prevalence and incidence by sex and race/ethnicity among Manhattan residents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ < 200 ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI < 80%). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, nonuse of steroids, higher body mass index, and unemployment were associated with nonadherence by drug level. Questionnaires classified 23.4% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with underreporting by patients, suggests that therapeutic drug monitoring is useful in this setting. (Trial registration: ClinicalTrials.gov: NCT01509989.)., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Objective: The spectrum of antinuclear antibodies (ANAs) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change is occurring in terminology to anticellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anticellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort., Methods: Anticellular antibodies were detected by IIF on HEp-2000 substrate using the baseline serum. Three serologic subsets were examined: ANA positive (presence of either nuclear or mixed nuclear/CMP staining), anticellular antibody negative (absence of any intracellular staining), and isolated CMP staining. The odds of being anticellular antibody negative versus ANA or isolated CMP positive was assessed by multivariable analysis., Results: A total of 1,137 patients were included; 1,049 (92.3%) were ANA positive, 71 (6.2%) were anticellular antibody negative, and 17 (1.5%) had an isolated CMP. The isolated CMP-positive group did not differ from the ANA-positive or anticellular antibody-negative groups in clinical, demographic, or serologic features. Patients who were older (odds ratio [OR] 1.02 [95% confidence interval (95% CI) 1.00, 1.04]), of white race/ethnicity (OR 3.53 [95% CI 1.77, 7.03]), or receiving high-dose glucocorticoids at or prior to enrollment (OR 2.39 [95% CI 1.39, 4.12]) were more likely to be anticellular antibody negative. Patients on immunosuppressants (OR 0.35 [95% CI 0.19, 0.64]) or with anti-SSA/Ro 60 (OR 0.41 [95% CI 0.23, 0.74]) or anti-U1 RNP (OR 0.43 [95% CI 0.20, 0.93]) were less likely to be anticellular antibody negative., Conclusion: In newly diagnosed systemic lupus erythematosus, 6.2% of patients were anticellular antibody negative, and 1.5% had an isolated CMP. The prevalence of anticellular antibody-negative systemic lupus erythematosus will likely decrease as emerging nomenclature guidelines recommend that non-nuclear patterns should also be reported as a positive ANA., (© 2018, American College of Rheumatology.)

Objectives: To assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications., Methods: This observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication., Results: A total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)]., Conclusion: CHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Single-cell RNA sequencing (scRNA-seq) has recently undergone rapid advances in the development of this technology, leading to high throughput and accelerating discovery in many biological systems and diseases. The single-cell resolution of the technique allows for the investigation of heterogeneity in cell populations, and the pinpointing of pathological populations contributing to disease. Here we review the development of scRNA-seq technology and the analysis that has evolved with the ever-increasing throughput. Finally, we highlight recent applications of scRNA-seq to understand the molecular pathogenesis of lupus and lupus nephritis., Competing Interests: Competing interests: None declared.

Objective: To characterize and compare the factors associated with tubulointerstitial inflammation (TII) and tubulointerstitial scarring, defined as interstitial fibrosis and/or tubular atrophy (IF/TA), in patients with lupus nephritis (LN)., Methods: We identified systemic lupus erythematosus patients who had renal biopsy results consistent with LN between 2005 and 2017. Clinical data were collected from medical records. Multivariable logistic regression models were fitted to assess factors associated with TII and with IF/TA (moderate-to-severe versus none/mild)., Results: Of 203 LN patients included, 41 (20%) had moderate-to-severe TII, 45 (22%) had moderate-to-severe IF/TA, and 21 (10%) had both. Multivariable logistic regression models showed that moderate-to-severe TII was associated with a shorter disease duration, African American race, proliferative LN, and an estimated glomerular filtration rate (eGFR) of <60 ml/minute/1.73 m 2 at the time of biopsy. Hydroxychloroquine use was associated with significantly lower odds of moderate-to-severe TII (odds ratio 0.27 [95% confidence interval 0.10-0.70], P = 0.008). Similar to TII, factors associated with moderate-to-severe IF/TA included proliferative LN and eGFR <60 ml/minute/1.73 m 2 at the time of biopsy. In addition, the presence of moderate-to-severe TII and older age was associated with moderate-to-severe IF/TA. None of the routinely available serologic markers-including anti-double-stranded DNA antibodies, anti-Ro/La antibodies, and low complement-were associated with tubulointerstitial damage., Conclusion: The use of hydroxychloroquine was strongly associated with less inflammation, while the presence of TII, proliferative LN, and low eGFR were major determinants of tubulointerstitial scarring. Identifying modifiable factors is critical for the development of better preventive and therapeutic strategies with the goal of improving survival in patients with lupus-related kidney disease., (© 2018, American College of Rheumatology.)

Objectives: The study aimed to determine if serum albumin at 12 months predicts long-term renal outcome at 48 months. Data from the NYU SAMPLE (Specimen and Matched Phenotype Linked Evaluation) Lupus Registry were used to compare the performance of albumin, anti-double-stranded DNA, C3/C4, proteinuria and haematuria., Methods: 82 patients with SLE with data at time of renal biopsy, at 12 months and at a second visit, and up to 48 months were included. The significance of each biomarker as a predictor of an adverse renal outcome (ARO), defined as doubling of serum creatinine, as creatinine >4 mg/dL if initial >2.5 mg/dL or ESRD, was evaluated in univariate and exploratory multivariable Cox proportional hazards models. Hazard ratios (HRs) for ARO with 95% CIs were generated. The receiver operating characteristic (ROC) curves at 48 months were used to identify the optimal cut-off point for albumin and proteinuria to predict ARO. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for albumin and proteinuria., Results: Serum albumin and proteinuria had statistically significant HRs for ARO (0.140 and 1.459, respectively). The model with both albumin and proteinuria indicated no additional independent contribution of proteinuria to albumin alone. The ROC curves identified cut-offs of 3.7 g/dL for albumin and 0.964 urine protein to creatinine ratio for proteinuria. Albumin had a sensitivity of 94%, specificity of 87%, PPV of 64% and NPV of 98%., Conclusions: This study demonstrates serum albumin >3.7 g/dL is a predictor of a favourable long-term renal outcome. These results support the inclusion of albumin as an outcome in lupus nephritis trials and treat-to-target guidelines., Competing Interests: Competing interests: None declared.

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.