Faculty Bibliography

OBJECTIVES/OBJECTIVE:A perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians' approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years. METHODS:Demographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively. RESULTS:At enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640-1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640-1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU-203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p<0.001). Overall, there was >91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2. CONCLUSION/CONCLUSIONS:In recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing.

OBJECTIVE:The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in SLE, but its association with hospitalizations has not been described. We estimated the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort. METHODS:Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in hospital. Multivariable models were adjusted for relevant baseline characteristics. RESULTS:The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (SD) age 35.7 (13.3) years and median (IQR) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08). During mean (SD) follow-up of 7.2 (3.7) years, 614 patients (39.6%) experienced 1570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up (Incidence Rate Ratio 1.21; 95%CI 1.13-1.30), adjusting for baseline age, sex, corticosteroid use, immunosuppressive use, ethnicity/location, SLE disease activity index 2000 (SLEDAI-2K), SLICC/ACR damage index (SDI), and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (Relative Rate 1.09; 95%CI 1.02-1.16). CONCLUSION/CONCLUSIONS:The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.

Background/Purpose Remission and low disease activity (LDA) are associated with decreased flares, damage, and mortality. However, little is known about the impact of disease activity states (DAS) on health care costs. We determined the independent impact of different definitions of remission and LDA on direct and indirect costs (DC, IC) in a multicentre, multiethnic inception cohort. Methods Patients fulfilling revised ACR classification criteria for SLE from 33 centres in 11 countries were enrolled within 15 months of diagnosis and assessed annually. Patients with >=2 annual assessments were included. Five mutually independent DAS were defined: 1) Remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone or immunosuppressants 2) Remission on-treatment: cSLEDAI-2K=0, prednisone <=5mg/d and/or maintenance immunosuppressants 3) LDA-Toronto Cohort (TC): cSLEDAI-2K<=2, without prednisone or immunosuppressants 4) Modified Lupus LDA State (mLLDAS): SLEDAI-2K<=4, no activity in major organs/systems, no new disease activity, prednisone <=7.5mg/d and/or maintenance immunosuppressants 5) Active: all remaining assessments Antimalarials were permitted in all DAS. At each assessment, patients were stratified into 1 DAS; if >1 definition was fulfilled per assessment, the patient was stratified into the most stringent. The proportion of time patients were in a specific DAS at each assessment since cohort entry was determined. At each assessment, annual DC and IC were based on health resource use and lost workforce/non-workforce productivity over the preceding year. Resource use was costed using 2021 Canadian prices and lost productivity using Statistics Canada age-and-sex-matched wages. To examine the association between the proportion of time in a specific DAS at each assessment since cohort entry and annual DC and IC, multivariable random-effects linear regression modelling was used. Potential covariates included age at diagnosis, disease duration, sex, race/ethnicity, education, region, smoking, and alcohol use. Results 1631 patients (88.7% female, 48.9% White, mean age at diagnosis 34.5) were followed for a mean of 7.7 (SD 4.7) years (table 1, Panel A). Across 12,281 assessments, 49.3% were classified as active (table 1, Panel B). Patients spending <25% vs 75-100% of their time since cohort entry in an active DAS had lower annual DC and IC (DC $4042 vs $9101, difference -$5060, 95%CI -$5983, -$4136; IC $21,922 vs $32,049, difference -$10,127, 95% -$16,754, -$3499) (table 2, Panel B&C). In multivariable models, remission and LDA (per 25% increase in time spent in specified DAS vs active) were associated with lower annual DC and IC: remission off-treatment (DC -$1296, 95%CI -$1800, -$792; IC -$3353, 95%CI -$5382, -$1323), remission on-treatment (DC -$987, 95%CI -$1550, -$424; IC -$3508, 95%CI -$5761, -$1256), LDA-TC (DC -$1037, 95%CI -$1853, -$222; IC -$3229, 95%CI -$5681, -$778) and mLLDAS (DC -$1307, 95%CI -$2194, -$420; IC -$3822, 95%CI -$6309, $-1334) (table 3, Model B). There were no differences in costs between remission and LDA. Conclusions Remission and LDA are associated with lower costs, likely mediated through the known association of these DAS with more favourable clinical outcomes

Objectives We previously reported in a single centre prevalent SLE cohort that antibodies against the cytokinesis-associated protein M-Phase Phosphoprotein 1 (anti-MPP-1) were associated with SLE-related cranial neuropathy (CN), a rare manifestation of neuropsychiatric SLE (NPSLE). The purpose of this study was to assess whether anti-MPP-1 is a biomarker for CN or other NPSLE manifestations using an international SLE inception cohort. Methods SLE patients fulfilling the updated 1997 ACR classification criteria for SLE were included. Anti-MPP-1 antibody testing was performed on baseline samples (within 15 months of diagnosis) or first annual assessment using an addressable laser bead immunoassay (ALBIA) with purified recombinant human protein with results expressed as median florescence units (MFU). Based on healthy controls, a dilution of >=1:500 MFU was considered positive. NPSLE manifestations occurring over the first 5 years of follow up were documented annually based on ACR case definitions using published NPSLE attribution rules1). The frequency of anti-MPP-1 positivity between patients with versus without each of the 19 NPSLE manifestations was compared using univariate logistic regression. For any NPSLE manifestations where anti-MPP-1 positivity differed between patients with versus without the manifestation, baseline demographic and clinical characteristics were compared using t-tests and twosample tests of proportions. For NPSLE manifestations associated with anti-MPP-1 positivity in the univariate analysis, multivariable logistic regression analysis using penalized maximum likelihood estimates was then performed to assess the relationship between anti-MPP-1 and the NPSLE manifestation, adjusting for age at anti-MPP-1 testing, female, White race/ethnicity, and significantly different baseline clinical characteristics. Results Seven hundred and ninety-five SLE patients were assessed; 29.8% were anti-MPP-1 positive, 88.7% female, and 52.1% White. The frequency of anti-MPP-1 positivity differed only for those with versus without CN (70.0% vs. 29.3%; odds ratio [OR] 5.16, 95%CI 1.44, 18.54) (table 1). Compared to patients without CN (n=785), patients with CN (n=10) were more likely to fulfill the ACR hematologic (difference: 23.9%, 95%CI 5.0%, 42.8%) and antinuclear antibody criteria (difference: 4.3%, 95%CI 2.9%, 5.8%) (table 2). (Table Presanted)In the multivariate analysis, anti-MPP-1 remained associated with CN (OR 5.24, 95%CI 1.44, 19.09) after adjusting for age at anti-MPP-1 testing, female, White race/ethnicity, hematologic disorder, and antinuclear antibody (table 3). Conclusion Anti-MPP-1 is a potential biomarker for CN. Although anti-MPP-1 is differentially expressed in a variety of neurological cells and tissues, the link to a pathogenic role requires further study