Faculty Bibliography

OBJECTIVES/OBJECTIVE:To assess the associations of severe non-adherence to HCQ, objectively assessed by HCQ serum levels, and risks of SLE flares, damage, and mortality over 5 years of follow-up. METHODS:The SLICC Inception Cohort is an international multicenter initiative (33 centers; 11 countries). Serum of patients prescribed HCQ for at least 3 months at enrollment were analyzed. Severe non-adherence was defined by a serum HCQ level <106 ng/ml or <53 ng/ml, for HCQ doses of 400 or 200 mg/d, respectively. Associations with the risk of a flare (defined as a SLEDAI-2K increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/ACR Damage Index (SDI) increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS:Of 1849 cohort subjects, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/ml (244-566); 48 patients (7.3%) had severe HCQ non-adherence. No covariates were clearly associated with severe non-adherence, which was however independently associated with both flare (OR 3.38; 95% CI 1.80-6.42) and an increase in the SDI within each of the first 3 years (HR 1.92 at 3 years; 95% CI 1.05-3.50). Eleven patients died within 5 years, including 3 with severe non-adherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION/CONCLUSIONS:Severe non-adherence was independently associated with the risks of an SLE flare in the following year, early damage, and 5-year mortality.

OBJECTIVE:To estimate direct and indirect costs associated with neuropsychiatric (NP) events in the Systemic Lupus International Collaborating Clinics inception cohort. METHODS:NP events were documented annually using American College of Rheumatology definitions for NP events and attributed to systemic lupus erythematosus (SLE) or non-SLE causes. Patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). Change in NP status was characterized by interstate transition rates using multistate modeling. Annual direct costs and indirect costs were based on health care use and impaired productivity over the preceding year. Annual costs associated with NP states and NP events were calculated by averaging all observations in each state and adjusted through random-effects regressions. Five- and 10-year costs for NP states were predicted by multiplying adjusted annual costs per state by expected state duration, forecasted using multistate modeling. RESULTS:A total of 1,697 patients (49% White race/ethnicity) were followed for a mean of 9.6 years. NP events (n = 1,971) occurred in 956 patients, 32% attributed to SLE. For SLE and non-SLE NP events, predicted annual, 5-, and 10-year direct costs and indirect costs were higher in new/ongoing versus no events. Direct costs were 1.5-fold higher and indirect costs 1.3-fold higher in new/ongoing versus no events. Indirect costs exceeded direct costs 3.0 to 5.2 fold. Among frequent SLE NP events, new/ongoing seizure disorder and cerebrovascular disease accounted for the largest increases in annual direct costs. For non-SLE NP events, new/ongoing polyneuropathy accounted for the largest increase in annual direct costs, and new/ongoing headache and mood disorder for the largest increases in indirect costs. CONCLUSION/CONCLUSIONS:Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.

OBJECTIVES/OBJECTIVE:A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes. METHODS:Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset. RESULTS:Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2. CONCLUSION/CONCLUSIONS:Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.

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.

Non-white people are more likely to develop systemic lupus erythematosus (SLE), yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-white populations. To address these issues, a conference was held in Bethesda, Maryland from October 15^th -16^th , 2019 entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and United States government representatives (the Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all of these groups, the organizers purposefully included people of non-white ancestry. Decreased participation of non-white SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-white patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.

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