Faculty Bibliography

Background Little is known about the economic burden of NP lupus. We estimated direct and indirect costs (DC, IC) associated with NP events attributed to SLE and non-SLE causes using multistate modelling. Methods Patients fulfilling ACR classification criteria for SLE from 31 centres in 11 countries were enrolled within 15 months of diagnosis. NP events were documented annually using ACR NP definitions and attributed to SLE or non-SLE causes. At each assessment and for SLE and non-SLE events, patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). The change in NP status characterized by transition rates between states was analyzed using multistate modelling (doi:10.1002/art.41876). At each assessment, annual DC and IC were based on health resource use and lost work-force/non-work-force productivity over the preceding year. Resource use was costed using 2021 Canadian prices and lost productivity using Statistics Canada age-and-sex specific wages. Costs associated with SLE and non-SLE NP states were calculated by averaging all observations in each NP state. Multiple regressions adjusted for possible confounding of age at diagnosis, sex, race/ethnicity, disease duration, geographic region, education, and smoking on the association of annual DC and IC and NP state. 5 and 10-year cumulative costs for NP states were predicted by multiplying adjusted annual costs for each state by the expected state duration, forecasted using multistate modelling. Results 1697 patients (89% female, 51% non-Caucasian race/ ethnicity, mean age at enrolment 35.1 years) were followed a mean of 8.8 years. 1971 NP events occurred in 956 patients, 32% attributed to SLE. For SLE NP events, annual DC were higher in those with new/ongoing vs no events ($10,809 vs $6715) (table 1). Annual and 5-yr IC were higher in new/ ongoing vs no events and new/ongoing vs resolved events (5- yr: new/ongoing vs no: $172,674 vs $136,970). For non-SLE NP events, annual IC were higher in new/ongoing vs no events, new/ongoing vs resolved events, and resolved vs no events and 5 and 10-yr IC were higher in new/ongoing vs no events (10-yr: new/ongoing vs no: $342,434 vs $279,874). For all NP states, IC exceeded DC 2.8 to 4-fold. Conclusion IC are 1.3-fold higher in patients with new/ ongoing vs no NP events. While DC trended higher in new/ ongoing events, they were not significantly higher across all NP states and times. Impaired productivity associated with ongoing and resolved NP lupus is substantial, contributing to the previously documented reduced quality of life

Background While there is overwhelming evidence for the beneficial role of hydroxychloroquine (HCQ) in SLE, little is known about its economic impact. We estimated annual direct, indirect, and total costs (DC, IC, TC) associated with HCQ use. Methods A subset of patients from the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) inception cohort were assessed annually between 2014 and 2019 for health resource use, lost work-force/non-work-force productivity and concurrent HCQ use. Resource use was costed using 2021 Canadian prices and lost productivity using Statistics Canada age-and-sex specific wages. At each assessment, HCQ dose over the past year and weight were documented and patients were stratified into 1 of 3 HCQ dosage groups: nonusers (0 mg/kg/day), low-intensity users (<= 5 mg/kg/day), or high-intensity users (>5 mg/kg/day). Costs associated with HCQ dose were calculated by averaging all observations within each dosage group. Multiple random effects linear regressions adjusted for the possible confounding of age at diagnosis, sex, race/ethnicity, disease duration, geographic region, education, alcohol use, and smoking on the association between annual DC and IC and HCQ dose. A possible mediating effect of disease damage (SLICC/ACR DI) on these associations was also investigated. Results 661 patients (89.4% female, 59.3% non-Caucasian race/ethnicity, mean age and mean disease duration at the start of economic assessments was 42.1 years and 9.5 years, respectively) were followed over a mean of 2.8 years. Across 1536 annual assessments, 36.1% of observations were provided by HCQ non-users, 43.1% by low-intensity users (mean dosage 3.4 mg/kg/day), and 20.8% by high-intensity users (mean dosage 5.9 mg/kg/day). Annual adjusted DC were higher in nonusers ($9599) versus low-intensity users ($6344) and highintensity users ($6333) (table 1). When disease damage was included in the regression, there were no significant differences in DC between dosage groups. While unadjusted IC were higher in non-users ($37,610) versus low-intensity users ($32,480) and high-intensity users ($31,418), adjusted IC did not differ. Adjusted TC were higher in non-users ($46,157) versus low-intensity users ($39,257) and high-intensity users ($37,634). Conclusion SLE patients reported higher adjusted annual DC and TC during periods of HCQ non-use versus periods of use, regardless of the intensity of use. There was no additional cost savings in those using high intensity dosages. The cost-savings effect of HCQ could potentially be partially mediated through reduced damage. In addition to its well-established therapeutic potential, there may be an economic imperative for HCQ use in SLE patients

Background Prior studies of SLE clusters based on autoantibodies have utilized cross-sectional data from single centers. We applied clustering techniques to longitudinal and comprehensive autoantibody data from a large multinational, multiethnic inception cohort of well characterized SLE patients to identify clusters associated with disease outcomes. Methods We used demographic, clinical, and serological data at enrolment and follow-up visits years 3 and 5 from 805 patients who fulfilled the 1997 Updated ACR SLE criteria and were enrolled within 15 months of diagnosis. For each visit, ANA, dsDNA, Sm, U1-RNP, SSA/Ro60, SSB/La, Ro52/ TRIM21, histones, ribosomal P, Jo-1, centromere B, PCNA, anti-DFS70, lupus anticoagulant (LAC), IgG and IgM for anticardiolipin, anti-b2GP1, and aPS/PT, and IgG anti-b2GP1 D1 were performed at a single lab (except LAC). K-means clustering algorithm on principal component analysis (10 dimensions) transformed longitudinal ANA/autoantibody profiles was used. We compared cluster demographic/clinical outcomes, including longitudinal disease activity (total and adjusted mean SLEDAI- 2K), SLICC/ACR damage index and organ-specific domains, SLE therapies, and survival, using one-way ANOVA test and a Benjamini-Hochberg correction with false discovery rate alpha=0.05. Results were visualized using t-distributed stochastic neighbor embedding. Results Four unique patient clusters were identified (table 1). Cluster 1, characterized by high frequency of anti-Sm and anti-RNP over time, was the youngest group at disease onset with a high proportion of subjects of Asian and African ancestry. At year 5, they had the highest disease activity, were more likely to have active hematologic and mucocutaneous involvement, and to be on/exposed to immunosuppressants/ biologics. Cluster 2, the largest cluster, had low frequency of anti-dsDNA, were oldest at disease onset, and at year 5, had the lowest disease activity, and were least likely to have nephritis and be on/exposed to immunosuppressants/biologics. Cluster 3 had the highest frequency of antiphospholipid antibodies over time, were more likely to be of European ancestry, have an elevated BMI, be former smokers, and by year 5, to have nephritis, neuropsychiatric involvement, including strokes and seizures (SLICC/ACR damage index). Cluster 4 was characterized by anti-SSA/Ro60, SSB/La, Ro52/TRIM21, histone antibodies, and low complements at year 5. Overall, survival of the 805 subjects was 94% at 5 years, and none of the clusters predicted survival. Conclusions Four SLE patient clusters associated with disease activity, organ involvement, and treatment were identified in this analysis of longitudinal ANA/autoantibody profiles in relation to SLE outcomes, suggesting these subsets might be identifiable based on extended autoantibody profiles early in disease and carry prognostic information

BACKGROUND:Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear antibodies (ANAs) are detected in many autoimmune diseases, up to 20% of healthy women are ANA-positive (ANA+) and most will never develop clinical symptoms. Furthermore, disease transition is higher among ANA+ African Americans compared with ANA+ European Americans. OBJECTIVE:We sought to determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals. METHODS:We comprehensively phenotyped immune profiles of African Americans and European Americans who are ANA-negative (ANA-) healthy, ANA+ healthy, or have SLE using single cell mass cytometry, next-generation RNA-sequencing, multiplex cytokine profiling, and phospho-signaling analyses. RESULTS:autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA- counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T-cell activation markers and higher plasma levels of IL-6 than did healthy ANA+ European Americans. CONCLUSIONS:We propose that this novel immune signature identified in ANA+ healthy European Americans may protect them from T-cell expansion, heightened activation of interferon pathways, and disease transition.

OBJECTIVES/OBJECTIVE:There is a paucity of data regarding healthcare costs associated with damage accrual in systemic lupus erythematosus (SLE). We describe costs associated with damage states across the disease course using multi-state modeling. METHODS:Patients from 33 centres 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 (ACR) 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 multi-state model. RESULTS:1687 patients participated, 88.7% female, 49.0% of Caucasian race/ethnicity, mean age at diagnosis 34.6 years (SD 13.3), and mean follow up 8.9 years (range 0.6-18.5). Annual costs were higher in those with higher SDIs (SDI ≥ 5: $22 006 2019 CDN, 95% CI $16 662, $27 350 versus SDI=0: $1833, 95% CI $1134, $2532). Similarly, 10-year cumulative costs were higher in those with higher SDIs at the beginning of the 10-year interval (SDI ≥ 5: $189 073, 95% CI $142 318, $235 827 versus SDI=0: $21 713, 95% CI $13 639, $29 788). CONCLUSION/CONCLUSIONS:Patients with the highest SDIs incur 10-year cumulative costs that are almost 9-fold higher than those with the lowest SDIs. By estimating the damage trajectory and incorporating annual costs, damage can be used to estimate future costs, critical knowledge for evaluating the cost-effectiveness of novel therapies.

OBJECTIVE:Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS:Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS:Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION:At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

BACKGROUND/PURPOSE/OBJECTIVE:In previously published work, atherosclerotic vascular events (AVE) occurred in approximately 10% of patients with SLE. We aimed to investigate the annual occurrence and potential risk factors for AVE in a multinational, multiethnic inception cohort of patients with SLE. METHODS:A large 33-centre cohort of SLE patients was followed yearly between 1999-2017. AVEs were attributed to atherosclerosis on the basis of SLE being inactive at the time of the AVE, and typical atherosclerotic changes on imaging or pathology, and/or evidence of atherosclerosis elsewhere. Analysis included descriptive statistics, rate of AVE's per 1000 patient-years, and univariable and multivariable relative risk regression models. RESULTS:Of the 1848 patients enrolled in the cohort, 1710 had at least one follow up visit after enrolment, for a total of 13,666 patient-years. Of 1710, 3.6% had one or more AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarials (HR: 0.54[95% CI 0.32, 0.91]) while higher AVE rates were associated with any prior vascular event (VE) (HR: 4.00[1.55,10.30]) and body mass index (BMI) >40 (HR: 2.74[1.04,7.18]) A prior AVE increased the risk for subsequent AVE (HR 5.42[3.17,9.27], p<0.001). CONCLUSION/CONCLUSIONS:The prevalence of AVE and rate of AVE accrual in this study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.

Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.

OBJECTIVE:The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC-FI values with damage accrual in the SLICC inception cohort. METHODS:The baseline visit was defined as the first at which both organ damage (SLICC/ACR Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36]) were assessed. Baseline SLICC-FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression estimated the association between baseline SLICC-FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. RESULTS:The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (standard deviation, SD) age 35.7 (13.3) years and median (interquartile range) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08) with a range of 0-0.51. Over a mean (SD) follow-up of 7.2 (3.7) years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC-FI values (per 0.05 increment) were associated with higher rates of increase in the SDI during follow-up (Incidence Rate Ratio [IRR] 1.19; 95% CI 1.13-1.25), after adjusting for age, sex, ethnicity/region, education, baseline SLEDAI-2K, baseline SDI, and baseline use of corticosteroids, antimalarials, and immunosuppressives. CONCLUSION/CONCLUSIONS:The SLICC-FI predicts damage accrual in incident SLE, which further supports the SLICC-FI as a valid health measure in SLE.