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OBJECTIVE: To phenotype SLE based on symptom burden (disease damage, system involvement and patient reported outcomes), with a specific focus on objective and subjective cognitive function. METHODS: SLE patients ages 18-65 years underwent objective cognitive assessment using the ACR Neuropsychological Battery (ACR-NB) and data were collected on demographic and clinical variables, disease burden/activity, health-related quality of life (HRQoL), depression, anxiety, fatigue and perceived cognitive deficits. Similarity network fusion (SNF) was used to identify patient subtypes. Differences between the subtypes were evaluated using Kruskal-Wallis and χ2 tests. RESULTS: Of the 238 patients, 90% were female, with a mean age of 41 years (s.d. 12) and a disease duration of 14 years (s.d. 10) at the study visit. The SNF analysis defined two subtypes (A and B) with distinct patterns in objective and subjective cognitive function, disease burden/damage, HRQoL, anxiety and depression. Subtype A performed worst on all significantly different tests of objective cognitive function (P

Drug development in lupus has improved over the past 10 years but still lags behind that of other rheumatic disease areas. Assessment of prospective lupus therapies in clinical trials has proved challenging for reasons that are multifactorial including the heterogeneity of the disease, study design limitations and a lack of validated biomarkers which greatly impacts regulatory decision-making. Moreover, most composite outcome measures currently used in trials do not include patient-reported outcomes. Given these factors, the Addressing Lupus Pillars for Health Advancement Global Advisory Committee members who serve on the drug development team identified an opportunity to convene a meeting to facilitate information sharing on completed and existing outcome measure development efforts. This meeting report highlights information presented during the meeting as well as a discussion on how the lupus community may work together with regulatory agencies to simplify and standardise outcome measures to accelerate development of lupus therapeutics.

ObjectiveWe investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals.MethodsUsing custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset.ResultsWe show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not.ConclusionOur findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing.

ObjectiveWe previously demonstrated the utility of the Automated Neuropsychological Assessment Metrics (ANAM) for screening cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) and developed composite indices for interpreting ANAM results. Our objectives here were to provide further support for the ANAM's concurrent criterion validity against the American College of Rheumatology neuropsychological battery (ACR-NB), identify the most discriminatory subtests and scores of the ANAM for predicting CI, and provide a new approach to interpret ANAM results using Classification and Regression Tree (CART) analysis.Methods300 adult SLE patients completed an adapted ACR-NB and ANAM on the same day. As per objectives, six models were built using combinations of ANAM subtests and scores and submitted to CART analysis. Area under the curve (AUC) was calculated to evaluate the ANAM's criterion validity compared to the adapted ACR-NB; the most discriminatory ANAM subtests and scores in each model were selected, and performance of models with the highest AUCs were compared to our previous composite indices; decision trees were generated for models with the highest AUCs.ResultsTwo models had excellent AUCs of 86 and 89%. Eight most discriminatory ANAM subtests and scores were identified. Both models demonstrated higher AUCs against our previous composite indices. An adapted decision tree was created to simplify the interpretation of ANAM results.ConclusionWe provide further validity evidence for the ANAM as a valid CI screening tool in SLE. The decision tree improves interpretation of ANAM results, enhancing clinical utility.

BackgroundThe evaluation of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive test (CAT) in adults with systemic lupus erythematous (SLE) is an emerging field of research. We aimed to examine the test-retest reliability and construct validity of the PROMIS CAT in a Canadian cohort of patients with SLE.MethodsTwo hundred twenty-seven patients completed 14 domains of PROMIS CAT and seven legacy instruments during their clinical visits. Test-retest reliability of PROMIS was evaluated 7-10 days from baseline using intraclass correlation coefficient (ICC (2; 1)). The construct validity of the PROMIS CAT domains was evaluated against the commonly used legacy instruments, and also in comparison to disease activity and disease damage using Spearman correlations. A multitrait-multimethod matrix (MMM) approach was used to further assess construct validity comparing selected 10 domains of PROMIS and SF-36 domains.ResultsModerate to excellent reliability was found for all domains (ICC [2;1] ranging from lowest, 0.66 for Sleep Disturbance and highest, 0.93 for the Mobility domain). Comparing seven legacy instruments with 14 domains of PROMIS CAT, moderate to strong correlations (0.51-0.91) were identified. The average time to complete all PROMIS CAT domains was 11.7 min. The MMM further established construct validity by showing moderate to strong correlations (0.55-0.87) between select PROMIS and SF-36 domains; the average correlations from similar traits (convergent validity) were significantly greater than the average correlations from different traits.ConclusionsThese results provide evidence on the reliability and validity of PROMIS CAT in SLE in a Canadian cohort.

ObjectiveCognitive function may change over time in patients with systemic lupus erythematosus (SLE), and cognitive function trajectories have not been well studied. We aimed to identify cognitive function trajectories in SLE and describe them with depressive symptoms trajectories, and we also aimed to identify baseline factors associated with class membership in the dual trajectories.MethodsLongitudinal data from the University of California San Francisco Lupus Outcomes Study were analyzed. Two outcome trajectories were studied jointly, the Hopkins Verbal Learning Test-Revised and the Center for Epidemiologic Studies Depression Scale (CES-D) (administered annually). Univariate/multivariable logistic regression analyses examined baseline factors associated with class memberships.ResultsA total of 755 patients were studied, and 4 latent classes were identified: 1) low CES-D scores and low cognitive scores (no depression plus cognitive impairment; 20%), 2) lowest CES-D scores and highest normal cognitive scores (no depression plus normal cognition; 48%), 3) highest CES-D scores and lowest cognitive scores (depression plus cognitive impairment; 9%), and 4) high CES-D scores and cognitive score at borderline (depression plus borderline cognition; 23%).ConclusionIn all, 4 distinct classes of dual cognitive function and depressive symptoms were identified. Persistently low cognitive performance in 28% of patients (classes 1 and 3) did not significantly improve over 7 years. Cognitive impairment was associated with depression status in 9% of patients (class 3). Other factors also predicted latent class membership: ethnicity, education, disease activity, physical functioning, and bodily pain. These results highlight the importance of periodic assessment of cognitive function and of different aspects relevant for assessing and managing cognitive function over time in SLE.

ObjectiveTo develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).MethodsThis international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects.ResultsThe 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.ConclusionThese new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.

Objective: Cognitive impairment (CI) in systemic lupus erythematosus (SLE) negatively impacts health‐related quality of life leading to activity limitations. This qualitative study aimed to (1) explore the effect of SLE‐related CI on activities of daily living and life role participation and (2) describe factors influencing activity restriction and life role participation. Methods: Semistructured, in‐depth interviews of lived experience of CI in SLE were conducted with 24 participants with SLE. Sociodemographic and clinical data, and objective and subjective cognitive function, were collected to characterize participants. A qualitative thematic content analysis was undertaken guided by a framework analytical approach. Results: Participants reported problems in multiple cognitive domains, with multiple perceived causes. CI was felt to impact work, social, domestic, and family life, health, and independence. Five overarching themes were represented in the data: (1) characterization of SLE‐reported CI, (2) perceived cause of CI, (3) perceived impact of CI on activities of daily living and life role participation, (4) adaptations for managing CI, and (5) influence of CI adaptations on activities of daily living and life role participation. Conclusion: This study provides a better understanding of the patient experience of CI in SLE, how it impacts their lives, and what coping strategies they employ. It highlights the long‐term challenges those with CI in SLE undergo and provides evidence for the urgent need to implement multidisciplinary treatment options. When managing CI, it may be beneficial to evaluate and understand available psychosocial support resources to help identify and reinforce relevant adaptations to improve health‐related quality of life. [ABSTRACT FROM AUTHOR]

Objectives Genetics plays an important role in SLE risk, as well as osteonecrosis (ON), a significant and often debilitating complication of SLE. We aimed to identify genetic risk loci for ON in people with childhood-onset (cSLE) and adult-onset (aSLE) SLE. Methods We enrolled participants from two tertiary care centres who met classification criteria for SLE. Participants had prospectively collected clinical data and were genotyped on a multiethnic array. Un-genotyped single nucleotide polymorphisms (SNPs) were imputed, and ancestry was inferred using principal components (PCs). Our outcome was symptomatic ON confirmed by imaging. We completed time-to-ON and logistic regression of ON genome-wide association studies (GWASs) with covariates for sex, age of SLE diagnosis, five PCs for ancestry, corticosteroid use and selected SLE manifestations. We conducted separate analyses for cSLE and aSLE and meta-analysed results using inverse-variance weighting. Genome-wide significance was P  < 5 × 10−8. Results The study included 940 participants with SLE, 87% female and 56% with cSLE. ON was present in 7.6% (n  = 71). Median age of SLE diagnosis was 16.9 years (interquartile range [IQR]: 13.5, 29.3), with median follow-up of 8.0 years (IQR: 4.2, 15.7). Meta-GWAS of cSLE and aSLE time-to-ON of 4 431 911 SNPs identified a significant Chr.2 SNP, rs34118383 (minor allele frequency = 0.18), intronic to WIPF1 (hazard ratio = 3.2 [95% CI: 2.2, 4.8]; P  = 1.0 × 10−8). Conclusion We identified an intronic WIPF1 variant associated with a 3.2 times increased hazard for ON (95% CI: 2.2, 4.8; P   =  1.0 × 10−8) during SLE follow-up, independent of corticosteroid exposure. The effect of the SNP on time-to-ON was similar in cSLE and aSLE. This novel discovery represents a potential ON risk locus. Our results warrant replication. [ABSTRACT FROM AUTHOR]

Objectives Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies. Methods Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z -score ≤−1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use. Results A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P  = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P  = 0.03]. MMF use was not associated with CD. Conclusion AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD. [ABSTRACT FROM AUTHOR]

Objective: To investigate the incidence of and factors associated with SARS–CoV‐2 testing and infection in immune‐mediated inflammatory disease (IMID) patients versus matched non‐IMID comparators from the general population. Methods: We conducted a population‐based, matched cohort study among adult residents from Ontario, Canada, from January 2020 to December 2020. We created cohorts for the following IMIDs: rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, systemic autoimmune rheumatic diseases, multiple sclerosis (MS), iritis, inflammatory bowel disease (IBD), polymyalgia rheumatica, and vasculitis. Each patient was matched with 5 patients without IMIDs based on sociodemographic factors. We estimated the incidence of SARS–CoV‐2 testing and infection in IMID patients and non‐IMID patients. Multivariable logistic regressions assessed odds of SARS–CoV‐2 infection. Results: We studied 493,499 patients with IMIDs and 2,466,946 patients without IMIDs. Patients with IMIDs were more likely to have at least 1 SARS–CoV‐2 test versus patients without IMIDs (27.4% versus 22.7%), but the proportion testing positive for SARS–CoV‐2 was identical (0.9% in both groups). Overall, IMID patients had 20% higher odds of being tested for SARS–CoV‐2 (odds ratio 1.20 [95% confidence interval 1.19–1.21]). The odds of SARS–CoV‐2 infection varied across IMID groups but was not significantly elevated for most IMID groups compared with non‐IMID comparators. The odds of SARS–CoV‐2 infection was lower in IBD and MS and marginally higher in RA and iritis. Conclusion: Patients across all IMIDs were more likely to be tested for SARS–CoV‐2 versus those without IMIDs. The risk of SARS–CoV‐2 infection varied across disease subgroups. [ABSTRACT FROM AUTHOR]

Objectives The objectives of this study were to determine the trajectories of depressive symptoms in patients with SLE and to identify baseline characteristics that are associated with a patient's trajectory of depression. Methods Data from the Lupus Outcomes Study at the University of California, San Francisco were analysed. Depressive symptomatology was assessed in years two through seven using the Center for Epidemiologic Studies Depression Scale (CES-D), with higher scores representing more severe depressive symptoms. Group-based trajectory modelling was used to determine latent classes of CES-D scores over time. Ordinal logistic regression analyses were performed to identify baseline characteristics associated with worse classes of depressive symptoms. Results CES-D scores for 763 individuals with SLE over 6 years were mapped into four distinct classes. Class 1 (36%) and class 2 (32%) comprised the largest proportion of the cohort and were defined by the lowest and low CES-D scores (no depression), respectively. Class 3 (22%) and class 4 (10%) had high and the highest scores (depression), respectively. Greater age [odds ratio (OR): 0.97, 95% CI: 0.96, 0.99] and higher education level (OR: 0.79, 95% CI: 0.70, 0.89) at baseline were associated with lower odds of membership in worse classes of depressive symptoms. Conversely, lower income (OR: 1.73, 95% CI: 1.03, 2.92), worse SF-36 physical functioning scores (OR: 1.12, 95% CI: 1.12, 1.13) and worse SF-36 bodily pain scores (OR: 1.58, 95% CI: 1.55, 1.61) were positively associated with membership in worse classes of depressive symptoms. Conclusion Four classes of depressive symptoms were identified in patients with SLE. Understanding the trajectories of depressive symptoms and the associated risk factors can aid in the management of these symptoms in individuals living with SLE. [ABSTRACT FROM AUTHOR]