Modelling long-term outcomes for patients with systemic lupus erythematosus.

BACKGROUND: New treatments for systemic lupus erythematosus (SLE) aim to improve tolerability and disease activity control over standard of care (SoC) treatment. SoC typically includes daily glucocorticoid (GC) which carries a risk of organ damage over time. This study sought to develop natural history models to identify predictors of long-term outcomes with current SoC SLE treatment. METHODS: Generalized linear and parametric accelerated failure time survival models (GLM) and parametric accelerated failure time (AFT) survival models were designed to identify predictors of disease activity, flare rate, GC use, organ damage, and mortality beyond the first year of treatment in patients with SLE. Models were run using a longitudinal retrospective analysis of prospectively collected Toronto Lupus Cohort (TLC) study data, collected between 1997 and 2020. Covariates of clinical and statistical significance were selected by bivariate- then multi-variate regression to find the model of best fit. FINDINGS: Of the 1255 subjects included, 89 % were female 89 % and 65 % Caucasian. Mean follow-up was 10·5 years. At first visit, 51 % of patients had moderate-to-severe disease activity (SLEDAI-2 K score ≥ 6). Mean organ damage scores gradually increased over the years following diagnosis. Median survival of the cohort was ∼35 years from study entry. In the GLM models, SLEDAI-2 K yearly average, and average GC dose were key for predicting change in SLEDAI-2 K, GC use/ dose, and flare (any/rate). Together, adjusted mean SLEDAI-2 K and GC dose were shown to be predictors of mortality and damage in at least 9 of 12 organ systems considered. INTERPRETATION: These comprehensive, longitudinal, predictive models show that disease activity and GC use are significant predictors of organ damage and mortality in a patient population with predominantly moderate to severe SLE. This deepens understanding of SLE natural history and underscores the need for new treatment approaches that reduce disease activity and GC use with an aim to improve long-term SLE outcomes. FUNDING: This study was funded by AstraZeneca.

In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

Disease course patterns in systemic lupus erythematosus.

BACKGROUND: Disease activity in systemic lupus erythematosus follows three different courses: long quiescent, relapsing remitting and persistently active. However, the patterns of disease course since diagnosis are not known. This study aimed to assess the prevalence and characteristics of such patterns over 10 years. PATIENTS AND METHODS: The inception cohort of the Toronto Lupus Clinic (≥10 year follow up, between visit interval ≤18 months) was investigated. Prolonged remission was defined as a clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 achieved within 5 years of enrolment and maintained for ≥10 years. The relapsing-remitting pattern was defined based on ≥2 remission periods (clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 for two consecutive visits). Patients with no remission were categorized as persistently active. Groups were compared for baseline characteristics, cumulative damage, flare rate, mortality and certain co-morbidities. RESULTS: Of 267 patients, 27 (10.1%) achieved prolonged remission, 180 (67.4%) relapsing-remitting and 25 (9.4%) persistently active. In total, 35 (13.1%) had only one remission period (hybrid). At enrollment, there were no differences regarding clinical and immunological variables. At 10 years, persistently active patients had accumulated significantly more damage than the prolonged remission and relapsing-remitting patients. Being of Black race and higher adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 over the first 2 years were associated with a more severe disease course. Relapsing-remitting and persistently active patients had an increased flare rate and accrued more osteoporosis, osteonecrosis and cardiovascular events. CONCLUSIONS: Approximately 70% of systemic lupus erythematosus patients followed a relapsing-remitting course, whereas 10% displayed prolonged remission and another 10% a persistently active course. Early response to treatment was associated with a less severe course and better prognosis.

Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus.

Background Systemic lupus erythematosus (SLE) patients are often treated with glucocorticoids, which place them at risk of bone loss. Objectives The objectives of this article are to determine: (1) the prevalence of low bone mineral density (BMD) and factors associated with low BMD and (2) the prevalence of symptomatic fragility fractures in inception patients of the Toronto Lupus Cohort (TLC). Methods Prospectively collected data from the TLC (1996-2015) of inception patients' first BMD were analyzed. For pre-menopausal women/males <50 years, BMD 'below expected range for age' was defined by Z-score ≤ -2.0 SD. For post-menopausal women/males age 50 or older, osteoporosis was defined by T-score ≤ -2.5 SD and low bone mass by T-score between -1.0 and -2.5 SD. Patients' BMDs were defined as abnormal if Z-score ≤ -2.0 or T-score < -1.0 SD, and the remainder as normal. Descriptive analysis and logistic regression were employed. Results Of 1807 patients, 286 are inception patients with BMD results (mean age 37.9 ± 13.7 years); 88.8% are female. The overall prevalence of abnormal BMD is 31.5%. In pre-menopausal women ( n = 173), the prevalence of BMD below expected range is 17.3%. In post-menopausal women ( n = 81), the prevalence of osteoporosis and low BMD are 12.3% and 43.2%, respectively. Age and cumulative dose of glucocorticoids are statistically significantly associated with abnormal BMD in multivariate analysis. Of 769 inception patients from TLC, 11.1% experienced symptomatic fragility fractures (peripheral and vertebral) over the course of their disease. Conclusion The prevalence of low BMD is high in SLE patients, and is associated with older age and higher cumulative glucocorticoid dose.

Impact of pulmonary disease on patient-reported outcomes and patient-performed functional testing in systemic lupus erythematosus.

OBJECTIVES: This study examines the effect of pulmonary disease on patient-reported outcomes (PROs) and patient-performed outcome (PPO) in systemic lupus erythematosus (SLE) patients at a single tertiary referral center. METHODS: Pulmonary function tests (PFTs), chest imaging, SLE-related damage, and disease activity were examined in 110 SLE patients. Presence was noted of abnormal PFTs, pleural disease, pulmonary hypertension (PH), pulmonary infarction, interstitial lung disease (ILD), and shrinking lung syndrome (SLS). PROs included the Medical Outcome Short Form-36 Health Survey, Pittsburgh Sleep Quality Index, Fatigue Severity Scale, Borg Dyspnea Scale, patient dyspnea and cough. The PPO of interest was the six-minute walk test (6MWT). Relationships amongst PROs, 6MWT, and pulmonary disease were studied. RESULTS: Pulmonary disease was present in 62 (56%) of 110 subjects: 54 (49%) abnormal PFT, 13 (12%) pleural disease, 12 (11%) ILD, 11 (10%) SLS and five (5%) PH. Dyspnea was the only PRO found to be significantly associated with pulmonary disease (P = 0.0004). Participants with pulmonary disease compared to those without had significantly reduced distance (P = 0.00015, 95% CI for mean 39-125 m) and predicted distance (P = 0.00001, 10%-26%) on 6MWT. CONCLUSIONS: Pulmonary disease is common in SLE and adversely impacts 6MWT distance and dyspnea without apparent influence on other PROs. The 6MWT may be a promising tool in the assessment of pulmonary disease in SLE.

SLEDAI-2K Responder Index 50 captures 50% improvement in disease activity over 10 years.

OBJECTIVES: To determine the frequency and the time to complete recovery identified by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the time to partial recovery identified by the SLEDAI-2K Responder Index 50 (SRI-50) in three laboratory systems over 10 years. METHODS: This is a retrospective analysis of the data available from the Toronto Lupus Clinic over the last 10 years. Patients with SLEDAI-2K renal, immunological and hematologic active descriptors were identified. The percentage of descriptors with partial and complete recovery was studied at one year and over the study period. Descriptive analysis and the Kaplan-Meier estimator were applied to study the time to partial and complete recovery. RESULTS: Of the 795 patients, 94% had an active system at some point during the study period. Partial recovery was shown in 66% of patients by SRI-50 for at least one descriptor over the study period. None of these partial findings identified would have been captured using SLEDAI-2K alone. The time to partial recovery identified by SRI-50 was shorter than the time to complete recovery identified by SLEDAI-2K. CONCLUSION: The SRI-50 is a valid responder index derived form SLEDAI-2K and is very helpful in identifying clinically important improvement in active laboratory descriptors in an efficient time.

SLEDAI-2K 10 days versus SLEDAI-2K 30 days in a longitudinal evaluation.

The objective of the study was to evaluate SLEDAI-2K 30 days over time and to compare with the original SLEDAI-2K 10 days. Forty-one patients seen at The University of Toronto Lupus Clinic were followed at monthly intervals for 12 months. The SLEDAI-2K score was completed twice, once for a 10-day window and again for a 30-day window using the same definitions for the descriptors. Four hundred and nineteen patient-visits in 41 patients were recorded for both SLEDAI-2K for a 10-day and a 30-day window. One hundred and fifty-one patient-visits had a SLEDAI-2K activity score of 0 and 268 patient-visits had varying levels of disease activity in the range 1-15. In all but one patient-visit there was an agreement between the SLEDAI-2K 10 days and 30 days. SLEDAI-2K 30 days scores were concordant with SLEDAI-2K 10 days scores, both in patients in remission and in patients with a spectrum of disease activity levels followed monthly over 1 year. SLEDAI-2K 30 days was validated against SLEDAI-2K 10 days in a longitudinal evaluation over 1 year. We recommend the use of SLEDAI-2K 30 days in clinical studies and clinical trials.

Burden of autoantibodies and association with disease activity and damage in systemic lupus erythematosus.

OBJECTIVES: To determine whether immunological burden of autoantibodies as reflected by the number of cumulative antibodies present at inception and after 3 and 5 years is associated with or predicts subsequent disease activity and damage in lupus. METHODS: Patients with SLE followed from inception at a single centre between 1992 and 2007 were included. Twelve autoantibodies were assayed in each patient at years 1, 3 and 5 of disease. The relationship between the burden of autoantibodies and outcomes, SDI (Systemic Lupus International Collaborative Clinics Damage Index), AMS (Adjusted Mean SLEDAI-2K) and AMS excluding anti-ds DNA (AMS-DNA) was evaluated as an association and as prediction. We determined the association between autoantibody burden and outcomes at years 1, 3 and 5 and the prediction using autoantibody burden at year 1 and year 3 to predict outcomes at years 3 and 5 respectively. RESULTS: Between 1992 and 2007, 235 inception patients were identified. Of these, 223, 163 and 129 patients had 10 or more autoantibodies tested at years 1, 3 and year 5 following diagnosis respectively. There was no association between the burden at years 1, 3 and 5 and outcome measures at years 1, 3 and 5 respectively. Furthermore, burden of autoantibodies at years 1 and 3 did not predict the outcome measures at years 3 and 5 respectively. CONCLUSIONS: Immunological burden in SLE at years 1, 3 or 5 as reflected by the number of autoantibodies found, was not associated with or predictive of subsequent disease activity or damage over time.

SLEDAI-2K for a 30-day window.

The aim of our study was to determine whether the SLEDAI-2K calculated using a timeframe of 30 days prior to a visit for clinical and laboratory variables was equivalent to the prescribed 10-day period. One hundred forty nine consecutive lupus patients seen over 9 weeks at the University of Toronto Lupus Clinic enrolled. The SLEDAI-2K score was completed twice, for a 10- and 30-day window. Forty patients had a classic SLEDAI-2K activity score of 0 and 109 patients had varying levels of disease activity ranging from 1 to 31. In all but one patient, there was agreement between the SLEDAI-2K 10 and 30 days. Thus SLEDAI-2K 30 days is similar to SLEDAI-2K 10 days, both in patients in remission and with a spectrum of disease activity levels. SLEDAI-2K 30 days may now be used to describe disease activity over the previous 30 days.

Oral bisphosphonates in treatment of transient osteoporosis.

Transient osteoporosis is a rare clinical syndrome of unknown etiology. It is believed that this syndrome is self-limiting; however, the data in the literature support the use of anti-resorptive agents that may reduce pain and decrease the duration of the illness. Herein, we describe two cases of transient osteoporosis of the hip and one case of transient osteoporosis of the knee where the use of oral bisphosphonates provided successful objective and subjective outcome.

Longitudinal myelitis in patient with systemic lupus erythematosus, homozygous prothrombin G20210A and heterozygous MTHFR 677T.

Longitudinal myelitis is an uncommon complication of systemic lupus erythematosus (SLE). We describe an unusual case of longitudinal myelitis and ischemic stroke in the presence of homozygous prothrombin G20210A, heterozygous MTHFR 677T mutations and the absence of antiphospholipid antibodies in a young woman with SLE.