Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study.

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission. METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission. FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare. INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months. FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

Seroprevalence and longevity of SARS-CoV-2 nucleocapsid antigen-IgG among health care workers in a large COVID-19 public hospital in Saudi Arabia: A prospective cohort study.

Seroprevalence of SARS-CoV-2 IgG among health care workers (HCWs) is crucial to inform infection control programs. Conflicting reports have emerged on the longevity of SARS-CoV-2 IgG. Our objective is to describe the prevalence of SARS-CoV-2 IgG in HCWs and perform 8 months longitudinal follow-up (FU) to assess the duration of detectable IgG. In addition, we aim to explore the risk factors associated with positive SARS-CoV-2 IgG. The study was conducted at a large COVID-19 public hospital in Riyadh, Saudi Arabia. All HCWs were recruited by social media platform. The SARS-CoV-2 IgG assay against SARS-CoV-2 nucleocapsid antigen was used. Multivariable logistic regression was used to examine association between IgG seropositive status and clinical and epidemiological factors. A total of 2528 (33% of the 7737 eligible HCWs) participated in the survey and 2523 underwent baseline serological testing in June 2020. The largest occupation groups sampled were nurses [n = 1351(18%)], physicians [n = 456 (6%)], administrators [n = 277 (3.6%)], allied HCWs [n = 205(3%)], pharmacists [n = 95(1.2%)], respiratory therapists [n = 40(0.5%)], infection control staff [n = 21(0.27%], and others [n = 83 (1%)]. The total cohort median age was 36 (31-43) years and 66.3% were females. 273 were IgG seropositive at baseline with a seroprevalence of 10.8% 95% CI (9.6%-12.1%). 165/185 and 44/112 were persistently IgG positive, at 2-3 months and 6 months FU respectively. The median (25th- 75th percentile) IgG level at the 3 different time points was 5.86 (3.57-7.04), 3.91 (2.46-5.38), 2.52 (1.80-3.99) respectively. Respiratory therapists OR 2.38, (P = 0.035), and those with hypertension OR = 1.86, (P = 0.009) were more likely to be seropositive. A high proportion of seropositive staff had prior symptoms 214/273(78%), prior anosmia was associated with the presence of antibodies, with an odds ratio of 9.25 (P<0.001), as well as fever and cough. Being a non-smoker, non-Saudi, and previously diagnosed with COVID-19 infection by PCR were statistically significantly different by seroprevalence status. We found that the seroprevalence of IgG against SARS-CoV-2 nucleocapsid antigen was 10.8% in HCWs at the peak of the pandemic in Saudi Arabia. We also observed a decreasing temporal trend of IgG seropositivity over 8 months follow up period.

Performance of the 2017 EUSTAR activity index in an scleroderma cohort.

Assessment of disease activity in systemic sclerosis (SSc) is limited by the absence of a fully validated, multisystem measure of disease activity. The European Scleroderma Trials and Research Group (EUSTAR) SSc activity index (EScSG-AI) was recently revised, and a validation study within the EUSTAR cohort was performed. In this study, we evaluated the performance of the revised EScSG-AI in an external Australian cohort. The association between the EScSG-AI and the physician global assessment of disease activity (PhGA), both collected prospectively at each annual visit over up to 12 years follow-up, was evaluated using Pearson's correlation coefficient and Cohen's kappa coefficient. Generalized linear modelling and time-dependent Cox regression analysis were performed to determine the association of disease activity measured by the EScSG-AI and the summed Medsger Severity Scale (MSS) and death, respectively. There was a moderate correlation between EScSG-AI and PhGA scores (r 0.42, p < 0.001) and moderate association between rising EScSG-AI and summed MSS (r 0.60, p < 0.001). High disease activity, measured by the EScSG-AI at any time during follow-up, was associated with a hazard ratio of 2.07 (95% CI 1.51-2.79) for mortality. The EScSG-AI has a moderate correlation with physician-assessed SSc disease activity. This suggests that the criterion and construct validity of the EScSG-AI are yet to be demonstrated in an external cohort of SSc patients. Key Points •There remains no gold standard measure of SSc disease activity. •The revised 2017 EUSTAR SSc disease activity index shows moderate correlation with physician-rated global disease activity. •Significant work remains to develop a validated multisystem measure of disease activity in SSc.

Laboratory investigation results influence Physician's Global Assessment (PGA) of disease activity in SLE.

OBJECTIVE: To evaluate the impact of laboratory results on scoring of the Physician Global Assessment (PGA) of disease activity in systemic lupus erythematosus. METHODS: Fifty clinical vignettes were presented via an online survey to a group of international lupus experts. For each case, respondents scored the PGA pre and post knowledge of laboratory test results (pre-lab and post-lab PGAs). Agreement between individual assessors and relationships between pre-lab and post-lab PGAs, and PGAs and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) were determined. Respondents were also asked about factors they incorporate into their PGA determinations. RESULTS: Sixty surveys were completed. The inter-rater PGA reliability was excellent (pre-lab intraclass correlation coefficient (ICC) 0.98; post-lab ICC 0.99). Post-lab PGAs were higher than pre-lab PGAs: median (IQR) pre-lab PGA 0.5 (1.05), post-lab PGA 1 (1.3) (p<0.001), with a median (IQR) difference of 0.2 (0.45). In general, all abnormal labs including elevated anti-double stranded DNA antibody level (dsDNA) and low complement impacted PGA assessment. Cases with weakest correlations between pre-lab and post-lab PGA were characterised by laboratory results revealing nephritis and/or haematological manifestations. Both pre-lab and post-lab PGAs correlated with SLEDAI-2K. However, a significantly stronger correlation was observed between post-lab PGA and SLEDAI-2K. Multiple factors influenced PGA determinations. Some factors were considered by an overwhelming majority of lupus experts, with less agreement on others. CONCLUSIONS: We found excellent inter-rater reliability for PGAs in a group of international lupus experts. Post-lab PGA scores were higher than pre-lab PGA scores, with a significantly stronger correlation with the SLEDAI-2K. Our findings indicate that PGA scoring should be performed with knowledge of pertinent laboratory results.

Incidence, Risk Factors, and Outcomes of Cancer in Systemic Sclerosis.

OBJECTIVE: To quantify the burden of cancer in systemic sclerosis (SSc). METHODS: Standardized incidence ratios (SIRs) and standardized mortality ratios relative to the general Australian population were derived. Cox proportional hazards regression was used to estimate survival in patients with SSc with cancer compared to patients without. Determinants of cancer were identified using logistic regression. Health care cost was quantified through cross-jurisdictional data linkage. RESULTS: This SSc cohort of 1,727 had a cancer incidence of 1.3% per year and a prevalence of 14.2%, with a SIR of 2.15 (95% confidence interval [95% CI] 1.84-2.49). The most common cancers were breast, melanoma, hematologic, and lung. Anti-RNA polymerase III (RNAP) antibody was associated with an increased risk of cancer (odds ratio [OR] 2.9, P = 0.044), diagnosed within 5 years of SSc disease onset. Calcium channel blockers were associated with a higher risk of overall cancer (OR 1.47, P = 0.016), breast cancer (OR 1.61, P = 0.051), and melanoma (OR 2.01, P = 0.042). Interstitial lung disease (ILD) was associated with lung cancer (OR 2.83, P = 0.031). Incident SSc cancer patients had >2-fold increased mortality compared to patients with SSc without cancer (hazard ratio 2.85 [95% CI 1.51-5.37], P = 0.001). Patients with SSc and cancer utilized more health care than those without cancer, with an excess annual health care cost of $1,496 Australian (P < 0.001). CONCLUSION: SSc carries an increased risk of developing cancer, particularly lung cancer associated with ILD, and breast cancer and melanoma occurring close to SSc disease onset in association with RNAP antibodies. Compared to those patients without cancer, patients with SSc and cancer had higher mortality and an increased health care cost, with an annual excess per patient cost of $1,496 Australian (P < 0.001).

Lupus Low Disease Activity State and Reduced Direct Health Care Costs in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Treat-to-target end points for systemic lupus erythematosus (SLE) have been assessed for their impact on damage accrual and flare, but whether they have an impact on the high health care utilization and costs in SLE has not been studied. The purpose of this study was to examine our hypothesis that the recently described lupus low disease activity state (LLDAS) would be associated with reduced health care cost. METHODS: Data from a single tertiary hospital longitudinal SLE cohort were assessed. Baseline demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K], physician global assessment [PhGA], and flare index), and medication use were evaluated, and direct health care utilization and cost data were obtained from hospital information systems. LLDAS was defined as previously published: briefly, SLEDAI-2K ≤4 with no new activity, PhGA ≤1, prednisolone ≤7.5 mg/day, and optimal standard immunosuppressive agents. Analysis was performed using multivariable linear regression. RESULTS: Two hundred SLE patients, contributing 357.8 person-years of observation, were included. A history of lupus nephritis was present in 42% of patients, and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index >0) was present at study commencement in 57.3% of patients. The mean ± SD annual direct medical cost per patient was US$7,413 ± 13,133/year. In multivariable analysis, increased cost was associated with the presence of baseline organ damage (41.7% increase; P = 0.009) and corticosteroid use (>7.5-15 mg/day: 55.7% increase; P = 0.02; and >15 mg/day: 202% increase; P < 0.001). In contrast, spending ≥50% of the observation period in LLDAS was associated with a 25.9% reduction in annual direct medical cost (P = 0.04). CONCLUSION: Greater time spent in LLDAS was associated with significantly reduced direct hospital health care costs among patients with SLE.

The cost-effectiveness of guideline-driven use of drug-eluting stents: propensity-score matched analysis of a seven-year multicentre experience.

Background: In routine clinical practice, the implantation of a drug-eluting stent (DES) versus a bare metal stent (BMS) for percutaneous coronary intervention (PCI) has been guided by criteria for appropriate use. The cost-effectiveness (CE) of adopting these guidelines, however, is not clear, and was investigated from the perspective of the Australian healthcare payer.Methods and results: Baseline and 12-month follow-up data of 12,710 PCI patients enrolled in the Melbourne Interventional Group (MIG) registry between 2004 and 2011 were analysed. Costs inputs were derived from a clinical costing database and published sources. Propensity-score-matching was performed for DES and BMS groups within sub-groups. Incremental cost-effectiveness ratios (ICERs) were evaluated for all patients, and sub-groups of patients with '0', 1, 2, or ≥3 indications for a DES. The incremental cost per target vessel revascularization avoided for the overall population was $24,683, and for patients with 0, 1, and 2 indications for a DES was $44,635, $33,335, and $23,788, respectively. However, for those with >3 indications, DES compared with BMS was associated with cost savings. At willingness to pay thresholds of $45,000-$75,000, the probability of cost-effectiveness of DES for the overall cohort was 71-91%, '0' indications, 49-67%, 1 indication, 56-82%, 2 indications, 70-90%, and ≥3 indications, 97-99%.Conclusions: The cost-effectiveness of DES compared with BMS increased with increasing risk profile of patients from those who had 1, 2, to ≥3 indications for a DES. When compared with BMS, DES was least cost effective among patients with '0' indications for a DES. Based on these results, selective use of DES implantation is supported. These findings may be useful for evidence-based clinical decision-making.

Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis.

OBJECTIVE: We sought to develop the first Damage Index (DI) in systemic sclerosis (SSc). METHODS: The conceptual definition of 'damage' in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort. RESULTS: Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort. CONCLUSIONS: Through the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

A randomised controlled trial of potential for pharmacologic prevention of new-onset albuminuria, hypertension and diabetes in a remote Aboriginal Australian community, 2008-2013.

INTRODUCTION: We conducted a double-blind randomised controlled trial in a remote-living Australian Aboriginal group at high risk for chronic disease to assess whether pharmacological treatment with angiotensin converting enzyme inhibitor (ACEi) could delay the onset of albuminuria, hypertension or diabetes in people currently free of those conditions. METHODS: Eligibility criteria in 2008 were age ≥18yr, blood pressure ≤140/90 mm/Hg, urinary albumin creatinine ratio (ACR) < 3.4 mg/mmol, normal levels of glycosylated haemoglobin, and, in females, infertility. A 2011 amendment allowed enrolment of fertile females using long-term contraception. "Treatment" was the ACEi perindopril arginine, or placebo, and participant events were ACR ≥3.4 mg/mmol and/or blood pressure >140/90 mm Hg and/or haemoglobin A1c >6.5%, and/or cardiovascular events. Results were analysed in 125 randomised participants who commenced treatment. RESULTS: Recruitment was low, especially of women, and dropout rates high: there were finally 60 and 65 people in the ACEi and placebo groups respectively. In females, there were no events among 10 in the ACEi group, versus 5 events among 17 in the placebo group, and longitudinal ACR, HbA1c and blood pressure levels supported probable benefit of ACEi. There was no benefit of ACEi in males, but a probable benefit on diabetes/hypertension events. With the genders combined, there was probable reduction of diabetes (zero vs 4 events, p = 0.068), and of diabetes or hypertension (zero vs 5 events, p = 0.037). DISCUSSION: In this high-risk population, ACEi probably delays development of albuminuria, diabetes and hypertension in females, and of non-ACR events overall. Repeat investigation with a larger sample size is warranted.

Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis.

BACKGROUND: Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality. METHODS: Clinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models. RESULTS: Of 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p < 0.001), anti-MPO positive vs anti-MPO negative (38.5% vs 13.6%, p = 0.006) and anti-PR3 positive vs anti-PR3 negative patients (44.4% vs 13.4%, p < 0.001). A higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%, p < 0.001) and the anti-PR3 positive groups (50.0% vs 23.4%, p = 0.009). In multivariable analysis, ANCA-positive status remained associated with ILD after adjusting for anti-Scl-70 antibodies. Pulmonary embolism (PE) was more common in ANCA-positive patients (8.6% vs 3.0%, p = 0.002) and anti-PR3-positive patients (16.7% vs 3.3%, p = 0.022). ANCA-positive status remained associated with PE in a multivariable analysis adjusting for anti-phospholipid antibodies. Kaplan-Meier analysis revealed increased mortality in ANCA-positive patients (p = 0.006). In Cox regression analysis, ANCA was associated with increased mortality, after adjusting for age and sex. CONCLUSIONS: ANCA is associated with increased prevalence of ILD and PE in SSc. ANCA should be tested in SSc, as it identifies individuals with worse prognosis who require close monitoring for adverse outcomes.

Factors associated with the availability of iodized salt at household level: a case study in Bangladesh.

OBJECTIVE: The availability of iodized salt in households remains low in Bangladesh, which calls for improving the salt iodization quality and its coverage. The present study assessed the socio-economic disparity in Bangladesh to characterize the availability of iodized salt at household level. DESIGN: Associations between different socio-economic factors and availability of iodized salt at household level were explored using Bayesian mixed-effects logistic models after adjusting the district- and cluster-level random effects. SETTING: Bangladesh Multiple Indicator Cluster Survey (MICS), 2012-13.ParticipantsHouseholds (sample size, n 50981). RESULTS: Results showed that 73·15 % of household salt samples were iodized to some extent although iodization level varied. According to the regression model, houses with young (adjusted odds ratio of posterior mean (OR) = 1·31; 95 % credible interval (CI) 1·09, 1·64) and educated (OR = 3·66; 95 % CI 3·25, 4·23) household heads had significantly higher likelihood of availability of iodized salt. In addition, iodized salt was less likely be found in poor and rural households, as urban households were 2·88 times (95 % CI 2·41, 3·34) more likely have iodized salt. Moreover, the regional locations of the households were an important component that contributed to the local iodized salt coverage. As per the district-wise distribution, the north-west part of Bangladesh and Cox's Bazar in the far south seemed to lack household-level iodized salt. CONCLUSIONS: Our findings suggest that iodized salt intervention should be promoted considering the area variations, which could potentially help policy makers to design interventions in the context of Bangladesh.

Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus.

OBJECTIVE: We evaluated the discriminant capacity of the Lupus Low Disease Activity State (LLDAS) in post-hoc analysis of data from the BLISS-52 and BLISS-76 trials of belimumab in systemic lupus erythematosus (SLE). METHODS: LLDAS attainment, discrimination between belimumab and placebo arms, and the effects in subgroups with high disease activity at recruitment were evaluated at week 52 using appropriate descriptive statistics, χ2 test and logistic regression. RESULTS: At week 52, for belimumab 10 mg/kg, 17.0% and 19.3% of patients who achieved a Systemic Lupus Erythematosus Responder Index-4 also attained LLDAS in BLISS-52 and BLISS-76, respectively. Significantly more patients attained LLDAS on belimumab 10 mg/kg compared with placebo (12.5% vs 5.8%, OR 2.32, p=0.02 for BLISS-52; 14.4% vs 7.8%, OR 1.98, p=0.04 for BLISS-76). In a subgroup analysis, the difference in week 52 LLDAS attainment between belimumab 10 mg/kg and placebo was greater in patients who had higher disease activity at baseline, compared with the overall group. CONCLUSIONS: LLDAS was able to discriminate belimumab 10 mg/kg from placebo in the BLISS-52 and BLISS-76 trials. Our findings support the validity of LLDAS as an outcome measure in SLE clinical trials.

On-Pump Beating Heart Versus Conventional Coronary Artery Bypass Grafting Early After Myocardial Infarction: A Propensity-Score Matched Analysis From the ANZSCTS Database.

BACKGROUND: Coronary artery bypass grafting (CABG) performed early after acute myocardial infarction (AMI) carries a high risk of mortality. By avoiding cardioplegic arrest and aortic cross-clamping, on-pump beating heart CABG (ONBEAT) may benefit patients requiring urgent or emergency revascularisation in the setting of AMI. We evaluated the early and long-term outcomes of ONBEAT versus conventional CABG (ONSTOP) utilising the ANZSCTS National Cardiac Surgery Database. METHODS: Between 2001 and 2015, 5,851 patients underwent non-elective on-pump CABG within 7 days of AMI. Of these, 77 patients (1.3%) underwent ONBEAT and 5774 (98.7%) underwent ONSTOP surgery. Propensity-score matching (with a 1:2 matching ratio) was performed for risk adjustment. Survival data were obtained from the National Death Index. RESULTS: Before matching, the unadjusted 30-day mortality was ONBEAT: 9/77 (11.7%) vs. ONSTOP: 256/5,774 (4.4%), p<0.001. Preoperative factors independently associated with the ONBEAT were: septuagenarian age, peripheral vascular disease, redo surgery, cardiogenic shock, emergency surgery and single-vessel disease. After propensity-score matching, 30-day mortality was similar (ONBEAT: 9/77 (11.7%) vs. ONSTOP: 16/154 (10.4%), p=0.85), as was the rate of major adverse cardiac and cerebrovascular events (ONBEAT: 17/77 (22.1%) vs. ONSTOP: 38/154 (24.7%), p=0.84). ONBEAT patients received fewer distal anastomoses and were more likely to have incomplete revascularisation (ONBEAT: 15/77 (19.5%) vs. ONSTOP: 15/154, (9.7%), p=0.03). Despite this, 12-year survival was comparable (ONBEAT: 64.8% (95% CI 39.4-82.4%) vs. ONSTOP: 63.6% (95% CI 50.5, 74.3%), p=0.89). CONCLUSIONS: ONBEAT can be performed safely in high-risk patients requiring CABG early after AMI with similar short and long-term survival compared to ONSTOP.

Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study.

BACKGROUND: Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. METHODS: In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. INTERPRETATION: Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions. FUNDING: UCB, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study.

BACKGROUND: Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. METHODS: In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45-0·76; p<0·0001) and subsequent flare (0·65, 95% CI 0·56-0·75; p<0·0001). Cumulative time in LLDAS was associated with improved outcomes: compared with patients with less than 50% of observed time in LLDAS, those with at least 50% of observed time in LLDAS had reduced risk of damage accrual (0·54, 0·42-0·70; p<0·0001) and flare (0·41, 0·35-0·48; p<0·0001). Similarly, increased durations of sustained LLDAS were associated with incremental reductions in the risk of damage accrual. The association of LLDAS with reduced damage accrual was observed regardless of pre-existing damage or disease activity at study entry. INTERPRETATION: LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. FUNDING: The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.