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BackgroundSurvival in systemic lupus erythematosus (SLE) has improved substantially in the last 50 years. The aim of the present study was to assess the evolution of the all-cause, cause-specific and age-specific standardised mortality ratios (SMRs) of patients with lupus in Ontario, Canada.Patients and methodsBetween 1971 and 2013, 1732 patients were followed in the Toronto Lupus Clinic. Causes of death were retrieved from death certificates, autopsy reports, hospital records or the records of the family physicians. They were categorised as atherosclerotic, infectious, malignancy, active lupus and others. For the calculation of the SMR (indirect standardisation method), data from the general population of Ontario, Canada were used (Statistics Canada).ResultsTwo hundred and forty-nine patients (205 women) died (infections 24.5%, atherosclerosis 15.7%, active lupus 13.3%, malignancy 9.6%); mean age was 53.2±16.6 years and mean disease duration 15.2±11.7 years. The all-cause SMR was substantially decreased from the 1970s (13.5, 95% CI 8.6 to 18.5) to recent years (2.2, 95% CI 1.4 to 3.1). Similar trends were observed for atherosclerosis, infections and malignancies over time. The all-cause age-specific SMR was particularly high in younger (19–39 years old) patients (SMR=12.4, 95% CI 9.7 to 15.1) as compared with individuals older than 40 years (SMR=3.1, 95% CI 2.6 to 3.6). The cause-specific SMR was also higher in younger patients, particularly for infections and malignancies.ConclusionsThe all-cause and cause-specific SMR significantly decreased over time, likely reflecting the advances in the management of SLE and certain comorbidities. The all-cause and cause-specific SMR was particularly high for younger patients (<40 years old).

Lupus nephritis (LN) affects up to 40% of patients with systemic lupus erythematosus (SLE) and leads to end stage kidney disease (ESRD) in 17–33% after 10 years.1 We have investigated a number of factors that have been shown to predispose to a more rapid progression to ESRD, including time to initial response to conventional therapy, number of flares during follow-up, duration of immunosuppressive therapy, unusual histologic patterns and patient compliance.In the Toronto Lupus Cohort of 418 patients with LN, 209 (50%) achieved remission within the first year from LN diagnosis, 102 (24.4%) within the 2nd and 3rd years, 70 (16.7%) after 3 years and 37 (8.9%) never achieved remission. Sixty-six patients (15.8%) developed advanced chronic kidney disease after 9.5 years on average. The 66 patients who progressed to ESRD had a longer time to complete remission (3.0 ± 3.4 vs 1.6 ± 2.1 yrs), more often had two or more flares (40 (60.6%) vs 117 (33.2%) and had a shorter median time on immunosuppressants from complete remission to outcome (2 yrs (0–7) versus 4 yrs (0–8)). These factors remained independently significant in a multivariable analysis accounting for multiple other relevant factors.Catastrophic progression to ESRD was also associated with unusual histologic patterns. Examples of these included thrombotic microangiopathy, interstitial inflammation added to the classic ISN classes, collapsing glomerulopathy, concomitant anti-GBM nephropathy and poor patient compliance.These findings emphasize the importance of achieving early remission as well as flare prevention with prolonged immunosuppressive use and attention to patient compliance to maximise renal survival in LN.ReferenceTektonidou MG, et al. Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and bayesian meta-analysis. Arthritis Rheumatol 2016 Jun;68(6):1432–1441.Learning ObjectivesExplain that shorter time to remission of LN protects against rapid progression to ESRDExplain that preventing flares in LN protects against rapid progression to ESRDExplain that longer duration of immunosuppressive therapy in LN protects against rapid progression to ESRDDescribe the unusual features of LN that might lead to catastrophic progression to ESRD

ObjectivesTo develop a Glucocorticoid Toxicity Index (GTI) to assess glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies.MethodsNineteen experts on GC use and outcome measures from 11 subspecialties participated. Ten experts were from the USA; nine from Canada, Europe or Australia. Group consensus methods and multicriteria decision analysis (MCDA) were used. A Composite GTI and Specific List comprise the overall GTI. The Composite GTI reflects toxicity likely to change during a clinical trial. The Composite GTI toxicities occur commonly, vary with GC exposure, and are weighted and scored. Relative weights for items in the Composite GTI were derived by group consensus and MCDA. The Specific List is designed to capture GC toxicity not included in the Composite GTI. The Composite GTI was evaluated by application to paper cases by the investigators and an external group of 17 subspecialists.ResultsThirty-one toxicity items were included in the Composite GTI and 23 in the Specific List. Composite GTI evaluation showed high inter-rater agreement (investigators κ 0.88, external raters κ 0.90). To assess the degree to which the Composite GTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared with case ranking by the Composite GTI, yielding excellent agreement (investigators weighted κ 0.87, external raters weighted κ 0.77).ConclusionsWe describe the development and initial evaluation of a comprehensive instrument for the assessment of GC toxicity.

ObjectivesA 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.MethodsDemographic, 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.ResultsCluster 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.ConclusionFour discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.

Damage accrual in patients with lupus is due to both the disease itself and the medications used to treat the disease, especially corticosteroids. The disease courses in patients with lupus vary, with most patients running a relapsing remitting course (RR), a smaller number pursue a permanently active (PA) course, and another minority running a monophasic (M) prolonged remission course.1 In an inception cohort of 232 patients followed for 10 years we found that 76% followed a RR course, 10.8% a PA course and 11.6% a M prolonged remission course. Despite disease activity over time being better controlled in the modern era, patients with RR lupus will spend almost half of their course with active disease, resulting in significant damage accrual over time. In an inception cohort of 73 patients followed for 15 years, with a mean duration on corticosteroids of 117 months, there was a progressive increase in damage and at 15 years with 80% of the damage items recorded being definitely or possibly corticosteroid related.2 Furthermore, it has been shown that early damage is a predictor of mortality. In 263 inception patients followed for 10 years, 190 (72%) had no early damage and 73 (28%) had early damage. In patients with early damage, 25% died within 10 years as compared to only 7.3% with no early damage (p= 0.0002).3 Thus, prevention of damage accrual is a key objective in the management of patients with lupus.We examined whether damage accrual over a 5-year period is reduced with the prior use of antimalarials. Of an inception cohort of 354 patients who had a first ACR/SLICC score of 0, 75 developed damage over the first 5 years and these were matched with 150 controls with no damage. Antimalarials were protective for damage accrual in the first 5 years supporting their use at diagnosis.4 Finally belimumab, the first biologic approved for the treatment of lupus, has been assessed for the prevention of long term damage accrual. Patients followed long term from the original belimumab trials, compared with propensity score matched patients from the University of Toronto Lupus cohort matching for 17 clinical variables, showed that belimumab reduced organ damage progression, slowed the rate of organ damage progression and reduced the magnitude of year-to-year organ damage.5Learning ObjectivesDescribe damage accrual and the nature of the damageDescribe how damage accrual is associated with mortalityDemonstrate that hydroxychloroquine protects against damage accrualDemonstrate that belimumab protects against damage accrualReferencesTselios K, Gladman DD, Touma Z, et al. Disease course patterns in systemic lupus erythematosus. Lupus. 2019;28(1):114–22.Gladman DD, Urowitz MB, Rahman P, Ibañez D, Tam LS. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol. 2003;30(9):1955–9.Rahman P, Gladman DD, Urowitz MB, Hallett D, Tam LS. Early damage as measured by the SLICC/ACR damage index is a predictor of mortality in systemic lupus erythematosus. Lupus. 2001;10(2):93–6.Ruiz-Arruza I, Gladman D, Ibanez D, Urowitz M. Antimalarials protect systemic lupus erythematosus patients from damage accrual during the first five years of the disease. Arthritis Rheum. 2012;64:S611.Urowitz MB, Ohsfeldt RL, Wielage RC, et al. Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis. Ann Rheum Dis. 2019;78(3):372–9.

Antimalarial myopathic toxicities may involve both skeletal and cardiac muscles. In skeletal muscle it is a deposition myopathy and in cardiac muscle there may be a direct chemical action toxicity or a deposition myopathy.In skeletal muscle there are isolated case reports of clinical myopathy and two prospective studies, one of 119 cases and the other of 21 cases.1 2 Both showed ±19% abnormal muscle enzymes. Clinical weakness was very uncommon but biopsies in 15 patients showed classic EM findings of antimalarial toxicity. All patients improved with cessation of antimalarials.In chemical toxicity of cardiac muscle, antimalarials may cause QTc prolongation. This is based on isolated case reports. In one cross sectional case series of 90 patients there was no difference in QTc between those on antimalarials and those not.3 There are no reports of sudden death in lupus patients starting antimalarials. Perhaps the more significant findings are related to the deposition of antimalarials in cardiac muscle resulting in antimalarial induced cardiomyopathy (AMIC). Clinical, serologic, imaging and biopsy features of this complication will be described in 8 patients recently seen in the University of Toronto Lupus Clinic.4 A systematic review of 47 patients with biopsy proven AMIC will be presented.5 Features of AMIC include morphologic/structural changes (biventricular/septal hypertrophy, bi-atrial enlargement); functional defects (impaired systolic and diastolic function); conduction disorders (RBBB, LAFB, cAVB/SSS); elevated biomarkers (troponins [cTnI], BNP, CPK). In 151 lupus patients with no prior history of heart disease we found 16 (10.6%) had abnormal cTni and/or BNP.6 Of these six were diagnosed with AMIC, five with other diagnoses and five do not yet have a definite diagnosis. Cardiac biomarkers should be ordered in patients who are older, have a decreased eGFR, have elevated CK without clinical myositis, and who have taken antimalarials for more than 5 years.Learning ObjectivesDescribe antimalarial muscle toxicity in skeletal and cardiac muscleDiscuss the possible association between antimalarial treatment and QTc prolongation and its possible consequencesDescribe antimalarial deposition in cardiac muscle and its consequencesDifferentiate the role of cardiac biomarkers in the early detection of antimalarial induced cardiomyopathyReferencesCasado E, Gratacos J, Tolosa C, et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis. 2006;65(3):385–90.Kalajian AH, Callen JP. Myopathy induced by antimalarial agents: the relevance of screening muscle enzyme levels. Arch Dermatol. 2009;145(5):597–600.Haj-Ali M, .Belmont H Hydroxychloroquine and QTc Prolongation in a Cohort of SLE Patients [abstract]. Arthritis Rheumatol. 2020;72:Tselios K, Deeb M, Gladman DD, et al. Antimalarial-induced Cardiomyopathy in Systemic Lupus Erythematosus: As Rare as Considered?J Rheumatol. 2019;46(4):391–6.Tselios K, Deeb M, Gladman DD, Harvey P, Urowitz MB. Antimalarial-induced cardiomyopathy: a systematic review of the literature. Lupus. 2018;27(4):591–9.Tselios K, Gladman DD, Harvey P, et al. Abnormal Cardiac Biomarkers in Patients with Systemic Lupus Erythematosus and No Prior Heart Disease: A Consequence of Antimalarials?J Rheumatol. 2019;46(1):64–9.

ObjectivesThe study (206347) compared organ damage progression in patients with systemic lupus erythematosus (SLE) who received belimumab in the BLISS long-term extension (LTE) study with propensity score (PS)-matched patients treated with standard of care (SoC) from the Toronto Lupus Cohort (TLC).MethodsA systematic literature review identified 17 known predictors of organ damage to calculate a PS for each patient. Patients from the BLISS LTE and the TLC were PS matched posthoc 1:1 based on their PS (±calliper). The primary endpoint was difference in change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to 5 years.ResultsFor the 5- year analysis, of 567 (BLISS LTE n=195; TLC n=372) patients, 99 from each cohort were 1:1 PS matched. Change in SDI score at Year 5 was significantly lower for patients treated with belimumab compared with SoC (−0.434; 95% CI –0.667 to –0.201; p<0.001). For the time to organ damage progression analysis (≥1 year follow-up), the sample included 965 (BLISS LTE n=259; TLC n=706) patients, of whom 179 from each cohort were PS-matched. Patients receiving belimumab were 61% less likely to progress to a higher SDI score over any given year compared with patients treated with SoC (HR 0.391; 95% CI 0.253 to 0.605; p<0.001). Among the SDI score increases, the proportion of increases ≥2 was greater in the SoC group compared with the belimumab group.ConclusionsPS-matched patients receiving belimumab had significantly less organ damage progression compared with patients receiving SoC.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein–Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future. Systemic lupus erythematosus is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Here, Kaul et al . highlight the heterogeneity of the disease, the management approaches and provide an outlook on the future research directions.

Obviously, the expected role for biologic therapy in lupus is to control disease activity and prevent damage and co-morbidities, but what is the evidence that we are not faring well in those areas?Over the past 5 decades there has been a dramatic improvement in survival rates for patients with systemic lupus erythematosus (SLE) perhaps due to a combination of earlier diagnosis, more effective treatments, recognition of important comorbidities and their earlier diagnosis and treatment. Currently, the 20-year survival rate is 80%!1 2 Standardised Mortality Ratios have decreased from over 14 in the 1970s to just over two in the 2000s.3 Furthermore, the cause of the 206 deaths in our cohort due to lupus was only 19% whereas deaths from atherosclerotic disease was 21.5% and from infection 34.6% neither of which would require a biologic.4 In terms of disease activity, in the first decade of disease the adjusted mean Systemic Lupus Erythematosus Disease Activity Index-2K (AMS) has decreased from 7.94 in the 1970s to 5.16 in the 2000s and the percentage of time on prednisone >7.5 mg was significantly lower, all indicating much improved control of disease. This is corroborated by the fact that patients are spending a significant portion of their disease over the first 10 years in clinical remission.So, if patients are surviving longer with less active disease and lower steroid therapy, are they suffering more co-morbidities? The prevalence of atherosclerotic vascular events has similarly declined over the past 4 decades in our cohort from a prevalence from 11.0% to 3.8% (an incidence of 0.44 per 100 patient years) an incidence seen also in the SLICC cohort. 5 This dramatic decrease is due to better control of lupus disease activity and also treatment of atherosclerotic risk factors.Finally, when one looks at the randomised controlled trials with biologics in lupus, more than a third of the placebo-treated patients who were getting standard of care achieved their respective primary endpoints. The difference in outcome in those getting biologics was only in the range 10% greater, hardly a major impact.In summary, lupus is being much better controlled, less steroid is being used, co-morbidities are less and biologics to date have had a minimal impact. A Minority of Lupus Patients Will Need a Biologic!Learning ObjectivesDescribe how lupus survival has improved dramatically in past 5 decadesExplain how mortality in lupus is now less related to lupus and more related to co-morbidities or infectionDemonstrate that lupus patients are currently spending more of their time in remission and on less corticosteroidsShow that the major co-morbidity atherosclerotic vascular disease has decreased dramaticallyReferencesPons-Estel GJ, Alarcon GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010;39(4):257–68.Urowitz MB, Bookman AA, Koehler BE, et al. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976;60(2):221–5.Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006;54(8):2550–7.Urowitz MB, Su J, Gladman DD. Atherosclerotic Vascular Events in Systemic Lupus Erythematosus: An Evolving Story. J Rheumatol 2019:jrheum.180986.Urowitz MB, Gladman DD, Anderson NM, et al. Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort. Lupus Sci Med 2016;3(1):e000143.

Objectives Type I interferons (IFNs) play an important role in the pathophysiology of systemic lupus erythematosus (SLE). While cross-sectional data suggest an association between IFN-induced gene expression and SLE disease activity, interest in this as a biomarker of flare has been tempered by a lack of fluctuation with disease activity in the majority of patients. This led us to question whether IFN-induced gene expression might instead be a biomarker of overall disease severity, with patients with high levels spending more time in an active disease state. Methods Levels of five interferon-responsive genes were measured in the whole peripheral blood at baseline visit for 137 SLE patients subsequently followed for 5 years. Log transformed values were summed to yield a composite IFN5 score, and the correlation with various disease outcomes examined. Receiver operator characteristic analyses were performed for outcomes of interest. Kaplan-Meier curves were generated to compare the proportion of flare-free patients with high and low IFN5 scores over time. Results The baseline IFN5 score was positively correlated with the adjusted mean SLE disease activity index-2000, number of flares, adjusted mean prednisone dose, and number of new immunosuppressive medications over the subsequent 5 years. Optimal cut-offs for the IFN5 score were determined using Youden’s index and predicted more severe outcomes with 57–67% accuracy. A high baseline IFN5 level was associated with a significantly increased risk of subsequent flare. Conclusions Measurement of the type I IFN signature is a useful tool for predicting the subsequent disease activity course.