Faculty Bibliography

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 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/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.

Background/Purpose : The impact of glucocorticoid (GC) use on major organ damage in SLE patients has not been formally studied by amalgamating the relevant data published in the literature over the past 40 years. We aimed to study the association between GC use and the occurrence of major organ damage in SLE patients by performing meta-analyses of observational studies published between 1970 and December 2018. Methods : Literature search on PubMed (from 1966 to December 2018) for prevalence and longitudinal studies which reported GC exposure (proportion of GC users in the cohort [%GC use] and/or GC use in defined doses) and the occurrence (prevalence/incidence) of major organ damage in SLE patients using the keywords cataract, cerebrovascular (CVA), stroke, cardiovascular (CVS), angina, myocardial infarction (MI), coronary artery bypass, osteoporosis, avascular necrosis (AVN) and osteonecrosis in respective combinations with lupus was conducted. Studies with sample size < 50 and observation duration < 12 months were excluded. The logit of the proportion of patients with disease damage was modelled as a random effect in the meta-analysis, which was employed to study the association between the proportion of patients with organ damage and variables of GC use (mean daily [mg/day] and cumulative [gm] prednisone [PDN] doses and %GC use). A 2-stage estimation of the random-effects logistic regression models was used with restricted maximum likelihood estimation. Univariate associations between organ damage and moderators were examined for statistical significance, and variables related to GC use were adjusted for SLE disease duration in multivariate models if their univariate P values were < 0.2. Results : Out of 8,882 publications screened, 212 articles involving 205,619 SLE patients were eligible for the metaanalyses (Figure 1), of which 97 were prevalence and 115 were longitudinal studies. Univariate analyses of prevalence studies revealed that mean daily PDN dose (odds ratio [OR]=1.10, p=0.007) and lower proportion of female in the cohort (OR=0.002, p=0.002) were associated with the prevalence of overall CVS events. Mean daily PDN dose (OR=1.52, p< 0.001) and %GC use (OR=2,255.2, p< 0.001) were associated with the prevalence of AVN. A significant association between cumulative PDN dose and prevalence of CVA was found after multivariate adjustment for SLE disease duration (OR=1.07, p=0.017). In longitudinal studies, a significant association was identified between cumulative PDN dose and incidence of cataracts after adjustment for SLE disease duration (OR=1.04, p=0.013). While the incidence of MI in SLE patients has dropped over the past 40 years (OR=0.94, p=0.002), it was associated with % GC use after adjustment for SLE disease duration (OR=8.18, p=0.012). Interestingly, significant univariate associations were found between antimalarial use and lower prevalence of MI (OR=0.05, p=0.002) and lower incidence of CVA (OR=0.20, p=0.032). Conclusion : Independent of SLE disease duration, cumulative PDN dose was associated with higher prevalence of CVA and incidence of cataracts, and higher incidence of MI was associated with overall GC use

Background/Purpose : Many studies of cancer risk in SLE are limited by small sample size or use of administrative data, which rely on billing code diagnoses instead of clinical data. No studies to date focused on incident SLE. We studied cancer risk in the largest-ever cohort of clinically confirmed incident SLE patients. Methods : Patients meeting ACR criteria for new-onset SLE (within 15 months of diagnosis) were enrolled into the SLICC Inception Cohort, across 32 centres. Patients are followed yearly using a standard protocol, with detailed data collection including SLE Disease Activity Index-2000 (SLEDAI-2K) and damage, and drugs in the past year. New cancer diagnoses are recorded by the examining physician at the annual study visit, and confirmed with chart review including pathology reports. Multivariate proportional hazard regression was performed, using baseline variables for demographics (age at SLE onset, sex, race/ethnicity), and time-dependent variables for drugs (corticosteroids, anti-malarial drugs, immunosup-pressive drugs), smoking, and SLEDAI-2K. As well as cancer over-all, we evaluated risk factors for the most common cancer types. Results : Of 1848 new-onset SLE patients enrolled between 1999-2011, 1668 had at least one follow-up; these were the sample for the current analysis. End date was the first of death, last visit, or end of study interval for this analysis (Aug. 2015). Baseline demographics are shown in Table 1. Over 14,215 years (mean 8.5 years) there were 60 cancers (incidence 4. 2 events per 1,000 patient-years). This included 12 breast cancers, 9 non-melanoma skin, 7 lung, 6 hematological, 5 melanoma, 5 prostate, 3 cervical, 3 renal, 2 gastric, 2 head and neck, 2 thyroid, and one each rectal, sarcoma, thymoma, and uterine. Almost half of the cancer cases (including all of the lung cancers) were associated with baseline smoking, versus only one-third of those patients who did not develop cancer. Univariate analyses of all cancer types suggested a higher risk of cancer among patients of white race/ethnicity and among those with the highest quartile of disease activity at cohort entry. However, the multivariate proportional hazard regression indicated that among SLE patients, the over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In those analyses, the effect of race/ethnicity was not clearly evident, and the point estimate for highest quartile of disease activity actually reversed to suggest a nonsignificant trend towards lower cancer risk. In the multivariate analyses specifically for breast cancer, age at SLE diagnoses remained a risk factor, and antimalarials were associated with a decreased risk. This effect of anti-malarials was not clearly seen for any other cancer type. For non-melanoma skin cancer, both age at SLE diagnosis and cyclophosphamide were strongly linked with risk. Conclusion : This is the first large, multicentre cohort study to clearly show how different cancer types in SLE are associated with specific risk factors. Additional follow-up may allow additional determination of the possible effects of disease activity and drugs on cancer subtypes

Background Little is known about the association of healthcare costs with damage accrual in SLE. We describe the costsassociated with damage progression using multi-statemodeling.Methods Patients fulfilling the revised ACR Classification Criteria for SLE from 32 centres in 11 countries were enrolledin the Systemic Lupus International Collaborating Clinics(SLICC) inception cohort within 15 months of diagnosis.Annual data on demographics, SLE disease activity (SLEDAI-2K), damage (SLICC/ACR Damage Index [SDI] if-6 monthsfrom diagnosis), hospitalizations, medications, dialysis, and utilization of selected medical/surgical procedures were collected.Annual health resource utilization was costed using 2017Canadian prices. Annual costs associated with SDI states wereobtained from multiple regressions adjusting for age, sex, race/ethnicity, and disease duration. As there were relatively fewtransitions to SDI states 5 11, these were merged into a singleSDI state. Five and 10 year cumulative costs were estimatedby multiplying annual costs associated with each SDI state bythe expected duration in each state, which was forecastedusing a multi-state model and longitudinal SDI data from theSLICC Inception Cohort (Bruce IN et al. Ann Rheum Dis2015;74:1706 13). Future costs were discounted at a yearlyrate of 3%.Results 1676 patients participated, 88.7% female, 49.2% Caucasian, mean age at diagnosis 34.6 years (SD 13.4), mean disease duration at enrollment 0.5 years (range 0 1.3 years), andmean follow up 7.8 years (range 0.6 16.9 years). Healthresource utilization and annual costs (after adjustment usingregression) were markedly higher in those with higher SDIs(SDI=0, annual costs $1847, 95% CI $1120 to $2574;SDI-5, annual costs $26 772, 95% CI $19 631 to $33 813).At SDI<=2, hospitalizations and medications accounted for97.1% of direct costs, whereas at SDI-3, dialysis was responsible for 55.0%.Five and 10 year cumulative costs stratified by baseline SDIwere calculated by multiplying the annual costs associatedwith each SDI by the expected duration in that state. Fiveand 10 year costs were greater in those with the highest SDIsat baseline (table 1).Conclusions Patients with the highest baseline SDIs incurannual costs and 10 year cumulative costs that are at least 10-fold higher than those with the lowest baseline SDI. By estimating the expected duration in each SDI state and incorporating annual costs, disease severity at presentation can beused to predict future healthcare costs, critical knowledge forcost-effectiveness evaluations of novel therapies

OBJECTIVE:We describe disease activity, damage, and the accrual of key autoantibodies in an inception systemic lupus erythematosus (SLE) cohort. METHODS:The Systemic Lupus International Collaborating Clinics (SLICC) International Research Network, comprising 27 centers from 11 countries, has followed an inception cohort of SLE patients yearly according to a standardized protocol. Of these patients, 298 were followed for a minimum of 5 years and constitute the study population. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and damage was assessed using the SLICC/American College of Rheumatology Damage Index (SDI). Antinuclear antibody (ANA), anti-DNA, and anticardiolipin antibody (aCL) levels and lupus anticoagulant were assessed yearly. Descriptive statistics were generated and repeated-measures general linear models were used to evaluate SLEDAI-2K and SDI over time between whites and nonwhites. RESULTS:Of the 298 patients, 87% were women, 55% were white, 12% were African American, 14% were Asian, 16% were Hispanic, and 2% were categorized as "other." At enrollment, the mean age was 35.3 years, the mean SLEDAI-2K score was 5.9, and the mean disease duration was 5.5 months. Mean SLEDAI-2K scores decreased in the first year and then remained low. SLEDAI-2K scores were significantly lower at each year in whites compared to nonwhites. Mean SDI scores increased progressively over 5 years; there was no significant difference between whites and nonwhites. As expected, ANA positivity was high and anti-DNA positivity was relatively low at enrollment, and both increased over 5 years. Although lupus anticoagulant increased slightly over 5 years, aCL positivity did not. CONCLUSION/CONCLUSIONS:Disease activity in newly diagnosed patients decreases over their first 5 years, while damage increases. Antibody positivity ran variable courses over this period.