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BackgroundThe BILAG–based Composite Lupus Assessment (BICLA) and SLE Responder Index ≥4 (SRI[4], based on SLEDAI-2K) are validated composite global measures of clinically meaningful improvement in SLE disease activity. BICLA and SRI(4) responses were endpoints in the phase 2b MUSE and phase 3 TULIP-1/-2 trials.1–3 In a post hoc analysis, more patients met both the BICLA and SRI(4) response criteria at Week 52 (dual responders) with anifrolumab 300 mg vs placebo across trials (MUSE: 48.5% vs 19.9%; TULIP-1: 42.2% vs 27.9%; TULIP-2: 43.4% vs 26.4%; all nominal P4 Whereas the clinical benefit of BICLA responses alone have been characterized,5 the added benefit of dual BICLA/SRI(4) responses remains unknown.ObjectivesTo understand the clinical benefits (SLE clinical assessments, patient-reported outcomes [PROs], and healthcare utilization) of having a dual BICLA/SRI(4) response vs a response for just one endpoint or nonresponse for both, irrespective of treatment assignment.MethodsThis was a post hoc analysis of pooled data from the randomized, 52-week, double-blind TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials in which patients with moderate to severe SLE despite standard therapy received intravenous anifrolumab (150/300 mg) or placebo every 4 weeks for 48 weeks.1,2 Patients were categorized as dual responders (met both BICLA and SRI[4] response criteria at Week 52), single responders (met one of either BICLA or SRI[4] response criteria), or dual nonresponders (did not meet either response criteria). SLE clinical assessments, PROs, and healthcare utilization through Week 52 were evaluated for each group. Statistical comparisons were conducted for dual responders vs single responders and dual nonresponders.ResultsPatient demographics and baseline characteristics were generally balanced across dual responders (n=288), single responders (n=122), and dual nonresponders (n=409). At Week 52, dual responders had greater improvements in SLE-related measures compared with dual nonresponders across all evaluated clinical, PRO, and healthcare utilization outcomes (Figure, A–E).Compared with single responders, dual responders had a significantly greater mean change from baseline in SLEDAI-2K score (−8.2 vs −5.1; nominal PPPPanel A); there was also a numerically greater proportion with ≥50% reduction in CLASI-A score (91% vs 76%; nominal P=0.078) (Panel B). Dual responders had a greater mean reduction in baseline oral glucocorticoid (GC) daily dose (−5.6 vs −3.4; nominal P=0.006) vs single responders (Panel A).For PROs, compared with single responders, dual responders had a greater mean change in baseline PtGA score (−17.7 vs −8.6; nominal P=0.001), and a higher proportion had clinically meaningful improvements from baseline to Week 52 in fatigue (FACIT-F; 56% vs 43%; nominal P=0.014) and SF-36 physical component scores (60% vs 34%; nominal PPanel C–D). Healthcare utilization (ED visits and hospitalizations) was lower in dual responders vs single responders; however, this comparison did not reach nominal significance (nominal P=0.462 and 0.311, respectively) (Panel E).ConclusionPatients with SLE with dual responses in two validated outcome measures have significantly better outcomes across a range of clinical, PRO, and healthcare utilization measures compared with dual nonresponders. The higher degree of improvement in disease activity, especially in arthritis, and the greater reduction in oral GC dose compared with single responders is reflected in improved patient well-being, physical functioning, and fatigue. Being a dual responder offers a profound and clinically meaningful outcome for both the clinician and patient.References[1]Furie R. Lancet Rheumatol. 2019;1:e208–19.[2]Morand EF. N Engl J Med. 2020;382:211–21.[3]Furie R. Arthritis Rheumatol. 2017;69:376–86.[4]Isenberg D. Ann Rheum Dis. 2021;80:586–7.[5]Furie R. Arthritis Rheumatol. 2021;73:2059–68.AcknowledgementsWriting assistance was provided by Matilda Shackley of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of InterestsIan N. Bruce Speakers bureau: GSK, UCB, Astra Zeneca, Consultant of: AstraZeneca, GSK, UCB, Aurinia, Eli Lilly, BMS, Grant/research support from: GSK, Janssen, Konstantina Psachoulia Shareholder of: AstraZeneca, Employee of: AstraZeneca, Emmanuelle Maho Employee of: AstraZeneca, David Isenberg Consultant of: AstraZeneca, Amgen, Servier, Eli Lilly, UCB, Merck Serono, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma, UCB, Consultant of: AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer, UCB, Grant/research support from: MSD, Pfizer, Roche, BMS, GSK, UCB, Richard Furie Speakers bureau: AstraZeneca, Genentech, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: GSK, Novartis, Paid instructor for: AstraZeneca, Biogen, Eli Lilly, Consultant of: AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Servier, Grant/research support from: Abbvie, AstraZeneca, Bristol Myers Squibb, GSK, Janssen, Catharina Lindholm Employee of: AstraZeneca, Micki Hultquist Shareholder of: AstraZeneca, J&J, Employee of: AstraZeneca, Raj Tummala Shareholder of: AstraZeneca, Employee of: AstraZeneca

BackgroundThe results from the double-blind BEAT-lupus trial comparing belimumab vs placebo, both after rituximab in systemic lupus erythematosus (SLE) have recently been reported (1). We sought to identify biomarkers of response to belimumab after rituximab to aid a personalised approach to therapy for SLE.ObjectivesTo identify biomarkers of clinical response to belimumab after rituximab in the BEAT-lupus trial.MethodsWe constructed a model utilising a range of clinical, routine and exploratory laboratory data, from the BEAT-lupus trial to identify variables at baseline (screening) that could predict a major clinical response (MCR, defined as reduction to BILAG C in all domains, steroid dose of ≤7.5mg/day & SLEDAI≤2, without anti-dsDNA antibody component) at 52 weeks. Relevant serum autoantibodies and cytokines were assayed by ELISA/Simoa, and interferon signatures and BAFF expression measured by RT-PCR. A linear mixed model was applied to longitudinal data collected during the trial stratified by treatment and clinical response. An independent cross-sectional lupus cohort was recruited to validate biomarker association with organ involvement.ResultsA major clinical response (MCR) was achieved in 48% (10 responders, 11 non-responders) of patients who received belimumab after rituximab compared to 35% (8 responders, 15 non-responders) in the placebo group (i.e. rituximab alone), added to tapered standard of care, at 52 weeks. Baseline serum IgA2 anti-dsDNA antibody levels emerged as the only positive predictor of attaining MCR in belimumab treated patients (AUROC 0.8, 95% confidence interval [CI] 0.7-1.0), but negatively predicted MCR in the placebo arm (AUROC 0.2, CI 0.1-0.4). At baseline, 77% and 85% of patients were positive for serum IgA2 anti-dsDNA antibodies in belimumab and placebo arms respectively, which reduced to 30% at 52 weeks in the belimumab group but remained unchanged with placebo (Fisher exact test, p=0.007). In striking contrast, the percentage of patients who remained IgG anti-dsDNA antibody positive from baseline to 52 weeks were similar between the belimumab and placebo group, despite the serum levels significantly falling in the belimumab group (1). A significant reduction in serum IgA2 anti-dsDNA antibody levels at 24 and 52 weeks from baseline was only observed in belimumab responders (Figure 1).Figure 1.Percentage change in serum IgA2 anti-dsDNA antibody levels through to 52 weeks stratified by clinical response to belimumab (after rituximab) and placebo (after rituximab) at 52 weeks.The number of circulating IgA2-secreting (but not total) plasmablasts (p=0.032) and T follicular helper cells (p=0.031) were significantly reduced at 52 weeks in the belimumab treated arm compared to placebo. Elevated serum IgA2 anti-dsDNA antibody levels were also associated with active renal disease irrespective of treatment arm (odds ratio, OR 3.2, CI 1.7-5.8, pConclusionIgA2 anti-DNA autoantibodies is a biomarker of response to belimumab after rituximab, and of active renal disease, in systemic lupus erythematosus. Our study reveals distinct molecular networks associated with renal and mucocutaneous involvement, and response to B cell targeted therapies, which could guide precision targeting of current therapies for this heterogenous disease.References[1]Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57.AcknowledgementsThis research was supported by Versus Arthritis (grant number 20873) and the UCLH Biomedical Research Centre (BRC). GSK provided belimumab free of charge, as well as additional funding. GSK had no role in this research and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Versus Arthritis and the UCLH BRC reviewed the relevant grant proposals and monitor progress of relevant aspects of the study but did not play any role in the analyses, interpretation of data, or decision to submit results.Disclosure of InterestsMuhammad Shipa: None declared, Liliana Santos Ribeiro: None declared, Dao Nguyen: None declared, Andrew Embleton-Thirsk: None declared, Mariea Parvaz: None declared, David Isenberg Consultant of: Received consultancy fees from Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB., Caroline Gordon Speakers bureau: Speakers’ bureau for GSK and UCB, Consultant of: Consultancy work from the Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB, Grant/research support from: Educational grant from UCB to Sandwell and West Birmingham Hospitals NHS Trust, Michael Ehrenstein Speakers bureau: Speakers’ bureau for GSK, Consultant of: Consultancy work for GSK, Grant/research support from: Part of this research was supported by a grant from GSK to University College London

BackgroundA major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously found ADA to rituximab (RTX) are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis (1). In addition, we demonstrated that ADA to RTX predict subsequent infusion related reactions (2). However, little is known regarding the long-term dynamics of ADA to RTX in patients undergoing treatment for SLE.ObjectivesIn this study we evaluated the longitudinal impact of ADA positivity with particular focus on; 1) Risk factors for development of ADA. 2) Impact of ADA on treatment response. 3) Influence of ADA on RTX drug kinetics over time. 4) The capacity of ADA to neutralise RTX.MethodsPatients with SLE undergoing treatment with RTX were recruited to this study (n=35). Serum samples were collected at the following intervals post-treatment; 1-3 months (defined as ‘early’ post-treatment), 6 months, 12 months, 36 months (n=114).Clinical and laboratory data was collected pre-treatment and at each follow-up time point. Response to treatment was assessed by improvement in SLEDAI-2K score from baseline and also according to BILAG as previously described (3).ADA were detected using an electrochemiluminescent immunoassay. Serum RTX levels were measured by ELISA. ADA status was defined according to the following patterns over time; persistently negative, persistently positive (0-15 AU/ml) and persistently high positive (≥16 AU/ml, upper quartile). A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n=38).ResultsADA to RTX were found to be persistently positive in 64.3% of patients over the 36-month follow-up period and there was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients had a younger age at diagnosis of SLE when compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p=0.002, Figure 1 A). Multivariate logistic regression found a 22% decrease in risk of ADA positivity for each addition year after diagnosis (p=0.03).Figure 1.ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 g/L vs 0.87 ± 0.30 g/L, p=0.026), which remained lower at each subsequent time point post-treatment up to 12 months post-treatment (Figure 1B).At 1-3 months post-RTX, patients who were ADA positive had a significantly lower circulating drug level than ADA negative (pIn terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (pBILAG defined relapse was more common at six months post-treatment in ADA positive patients (22%) and ADA highly positive patients (33%) than those who were ADA negative (in which there were no cases of relapse within the first six months, Figure 1 F). At 12-months post-RTX, a higher rate of BILAG defined Major Response was seen in those who were ADA negative (80%) when compared with ADA positive (44%) and high positive (36%) as shown in Figure 1 G.Finally, antibodies derived from all ADA positive samples (38/38) were found to neutralise RTX in vitro.ConclusionADA to RTX were common and persisted over the 36-month period of this study. ADA associated with earlier serum drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment in clinical practice.References[1]Faustini F et al. Arthritis research & therapy. 2021;23(1):211[2]Wincup C et al. Annals of the rheumatic diseases. 2019;78(8):1140-2[3]Md Yusof MY et al Annals of the rheumatic diseases. 2017;76(11):1829-36Disclosure of InterestsNone declared

BackgroundAtacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. APRIL-SLE was a double-blind, placebo-controlled, Phase 2 study that randomized patients with moderate-to-severe systemic lupus erythematosus (SLE) to atacicept 75 mg, atacicept 150 mg, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks.ObjectivesThe primary results of the APRIL-SLE study – the effect of atacicept compared to placebo in preventing new flares in patients with moderate-to-severe SLE – have been reported (Isenberg et al., 2013). We performed a post hoc analysis to describe the effect of atacicept compared to placebo on measures of renal function in patients with SLE; this effect has not been reported previously.MethodsThe APRIL-SLE study excluded patients with moderate to severe glomerulonephritis, as defined by either of the following: urinary protein/creatinine ratio (UPCR)>1 mg/mg and/or hematuria or a significant renal impairment as defined by estimated glomerular filtration rate (eGFR)ResultsIn total, 111 patients in the placebo group, 112 patients in the atacicept 75 mg group, and 62 patients in the atacicept 150 mg group completed 52 weeks of treatment. The eGFR time course was stable for the atacicept groups compared to a 4.4% decline in the placebo group from baseline at week 52 (Figure 1 and Table 1). UPCR from baseline at week 52 declined in the atacicept groups and increased in the placebo group.Table 1.Median Percent Change from Baseline of Estimated Glomerular Filtration Rate (eGFR) and Proteinuria at Week 52 – Safety Analysis SetVariablePlaceboAtacicept 75 mgAtacicept 150 mgeGFR (mL/min)n=110n=111n=62 bmedian-4.35-1.490.57UPCR (mg/mg)n=108n=108n=63median6.29-6.27-12.72UPCR (mg/mg) an=12n=15n=8median26.11-54.42-12.15eGFR=estimated glomerular filtration rate; UPCR=urinary protein/creatinine ratio.aAmong patients with screening UPCR ≥0.2 mg/mg.bEnrollment in the atacicept 150 mg arm was discontinued prematurely (described in Isenberg et al., 2015).Figure 1.Median Change from Baseline in eGFR.eGFR= estimated glomerular filtration rate; IQR=interquartile rangeConclusionResults from this double-blind, placebo-controlled, Phase 2 study suggest a potential for improved renal function with atacicept treatment of patients with moderate-to-severe SLE.References[1]Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015;74(11):2006-15. Erratum in: Ann Rheum Dis. 2016 May;75(5):946.Disclosure of InterestsDavid Isenberg Consultant of: Professor Isenberg has consulted for Veratx, Servier, Astro-Zeneca, Idorsia, Merck Serono, and Amgen. His honoraria are passed onto a local arthritis charity., Celia J. F. Lin Shareholder of: Dr. Lin is an employee of Vera Therapeutics, Inc., Employee of: Dr. Lin is an employee of Vera Therapeutics, Inc., Amy Kao Shareholder of: Dr. Kao own stocks of Merck KGaA, Darmstadt, Germany, Employee of: Dr. Kao is an employee of EMD Serono Research & Development Institute, Inc (a business of Merck KGaA), Aida Arselan Aydemir Employee of: Ms. Aydemir is an employee of EMD Serono Research & Development Institute, Inc (a business of Merck KGaA), Caroline Gordon Speakers bureau: Dr. Gordon reports personal fees for speakers bureau from UCB, Consultant of: Dr. Gordon reports personal fees for honoraria from consultancy work from the Center for Disease Control and Prevention, Amgen, Astra-Zeneca, AbbVie, EMD Serono, MGP, Sanofi, and UCB, Grant/research support from: Dr. Gordon reports an educational grant from UCB to Sandwell and West Birmingham Hospitals NHS Trust that supported previous research work unrelated to any specific drug (last payment July 2019).

BackgroundCardiovascular disease (CVD) is a leading cause of mortality in patients with systemic lupus erythematosus (SLE, female:male ratio of 9:1) through accelerated atherosclerosis, the build-up of lipids and inflammation in the major artery walls, compared to age and sex matched healthy individuals. This is due to chronic inflammation, dyslipidaemia and other cardiometabolic defects that exacerbate with age (1). SLE in women aged of 35-44 increases the risk of coronary artery disease by 50 times and there is a 100-300-fold increased CVD-related mortality risk in young patients that develop SLE before the age of 18. Investigating metabolic defects in young patients and how they progress with age could help us understand the progressive mechanisms of atherosclerosis in SLE.ObjectivesThis study investigated detailed changes in the metabolomic profile of female patients with SLE and matched healthy controls across age.MethodsSerum NMR metabolomics (>250 metabolites, Nightingale) covering glycolysis metabolites, amino acids and 130 lipid measures was performed on serum from a cohort of female SLE patients (n=164, 13-72 years of age, median 35) and matched healthy controls (HCs, n=120, 15-76 years of age, median 36) and analysed by linear regression and Venn analysis. Multiple t-tests (corrected for multiple comparisons by false discovery rate) were used to assess unique metabolic changes by age group between SLE patients and HCs (≤25, n=62/43; 26-49, n=50/46; ≥50, n=52/31) and dysregulated metabolic pathways were assessed using metaboanalyst software. The metabolic impact of disease activity measures and treatments was assessed by Spearman correlations and unpaired t-tests respectively.ResultsTwenty-five metabolites were significantly altered in all SLE age groups compared to HCs, dominated by atheroprotective high density lipoprotein (HDL) subsets and their surface-bound peptide, apolipoprotein(Apo)A1, all of which were significantly decreased in SLE compared to HCs (pSeparately, metabolites associated with the glycolysis pathway (p=0.004, metaboanalyist), including acetone, citrate, creatinine, glycerol, lactate and pyruvate, had significant positive correlations with age in SLE patients, but not in HCs. These metabolites were not significantly associated with disease activity measures. However, pyruvate (p=0.01) and lactate (p=0.009) were significantly upregulated in prednisolone treated patients, whilst citrate (p=0.002) and creatinine (p= 0.005) were downregulated in hydroxychloroquine treated patients.ConclusionIncreasing HDL (ApoA1) levels whilst maintaining low disease activity in patients with SLE from a young age could improve cardiometabolic risk outcomes. This could be achieved through improved nutrition, lipid targeted therapies and better treatment strategies. Focusing on understanding and monitoring biomarkers of the glycolytic pathway could aid treatment decisions and help avoid adverse metabolic effects of current anti-inflammatory therapies in SLE (1).References[1]Robinson G.A, Pineda-Torra I, Ciurtin C, Jury E.C. Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. J Clin Invest. 2022;132(2):e148552. https://doi.org/10.1172/JCI148552.AcknowledgementsThe authors would like to thank all of the patients and healthy blood donors, as well as Prof. Arne Akbar and Dr. Chris Wincup for additional patient and healthy donor samples.Disclosure of InterestsNone declared.

BackgroundThe MSK components of the BILAG and SLEDAI have limited sensitivity, specificity and responsiveness.ObjectivesTo develop a better disease activity tool for MSK lupus.Methods“LAMDA” was derived using data from the multicentre USEFUL study (PMID:33792659); 133 patients with inflammatory MSK pain received intramuscular depomedrone then were assessed for 66/68 SJC/TJC, BILAG-2004, SLEDAI-2K, physician MSK-VAS, inflammatory markers, patient pain and disease-activity-VAS and MSK-ultrasound. Baseline variables were modelled against US using penalized (Lasso) regression. For validation we evaluated: (i) responsiveness at week 6 in USEFUL and (ii) association with quality of life and treatment decision in an independent study (n=100).ResultsLAMDA was a composite of SJC, patient-MSK-pain-VAS, physician-MSK-disease-activity-VAS and ESR ranging from 0 to 26.5. Response effect size was greater for the LAMDA (0.37) than the BILAG-MSK (0.31), SLEDAI-MSK (0.27) and total US score (0.33). With active US at baseline, LAMDA’s effect size was 0.42.In the validation study LAMDA score correlated with better physical function (R = -0.49, pConclusionLAMDA is a continuous disease activity instrument for MSK lupus that is sensitive to imaging-synovitis without swelling, more responsive than other instruments and correlates with quality of life and treatment decision. LAMDA may improve the ability of clinicians to monitor and treat MSK lupus, and determine the efficacy of therapies in clinical trials.AcknowledgementsFunding: Lupus UK and NIHRDisclosure of InterestsKhaled Mahmoud: None declared, Ahmed Zayat: None declared, Md Yuzaiful Md Yusof: None declared, Lee-Suan Teh: None declared, Shah Khan: None declared, Chee-Seng Yee: None declared, David D’Cruz: None declared, Nora Ng: None declared, David Isenberg: None declared, Coziana Ciurtin: None declared, Philip G Conaghan: None declared, Paul Emery: None declared, Christopher John Edwards: None declared, Elizabeth Hensor: None declared, Edward Vital Speakers bureau: GSK, AstraZeneca, Consultant of: GSK, AstraZeneca, Roche, Aurinia, Lilly, ILTOO, Novartis, Grant/research support from: AstraZeneca, Sandoz

BackgroundAntiphospholipid syndrome (APS) patients experience damage accrual (1) but correlation with mortality is rarely reported. In systemic lupus erythematosus (SLE), early damage accrued in the first year of disease is a predictor of mortality (2).ObjectivesTo determine whether damage accrued within the first year after APS onset as measured by the Damage Index for APS (DIAPS) predicts mortality.MethodsSingle-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria). The disease onset was determined as the time the first thrombotic event related to APS was diagnosed. Annual DIAPS assessments were determined for each patient. Early damage was considered to be a score ≥1 at the initial assessment (six months). DIAPS is shown as median (interquartile range [IQR]). Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality.ResultsA total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) with a median age at APS onset of 40 years (IQR 51 - 28) were followed for up to 43 years (median 10 years). Cumulative damage developed in 143 (73.6%) patients with a median DIAPS of 1 (IQR 2 - 0) at the last visit. Early damage was present in 69 (35.0%) patients. Patients with early damage had similar sex distribution (p=0.733), age at disease onset (p=0.526) and median time of follow-up (p=0.181) comparing to those without early damage. Secondary APS (SAPS) (odds ratio [OR] 1.89, 95% CI 1.03 - 3.48, p=0.041) and having a first arterial event (OR 7.24, 95% CI 3.74 - 14.03, pp=0.009), male sex (p=0.008) and age at onset ≥40years (p=0.001) were risk factors for death (Table 1). Early damage was not associated with death (hazard ratio [HR] 1.65, 95% CI 0.73 - 3.78, p=0.231; Figure 1: survival curve) even after adjusting individually for APS category (secondary, p=0.446), sex (male, p=0.374), age at onset ≥40years (p=0.115) and type of event (arterial, p=0.555).Table 1.Predictors of mortality.Crude analysisAdjusted analysis†HR (95% CI)p-valueHR (95% CI)p-valueMale sex3.14 (1.35 – 7.33)0.0081.46 (0.63 – 3.36)0.374Age at APS onset ≥ 40 years5.34 (1.9 – 14.53)0.0011.95 (0.85 – 4.50)0.115Caucasian0.95 (0.35 – 2.57)0.9181.61 (0.70 – 3.70)0.257Secondary APS3.07 (1.32 – 7.12)0.0091.38 (0.59 – 3.20)0.446First event (arterial)1.85 (0.79 – 4.27)0.1511.32 (0.53 – 3.32)0.555Early damage1.65 (0.73 – 3.78,0.231--† In this column, we present the Early Damage hazard ratio and 95% confidence intervals for death adjusted for the variable in each row. Statistically significant values are presented in bold. APS, antiphospholipid syndrome; CI, confidence interval; DIAPS, Damage Index for Antiphospholipid Syndrome; HR, hazard ratio.Figure 1.Survival probability in patients with and without early damage.ConclusionUnlike SLE, early damage accrual accessed by DIAPS is not a predictor of mortality regardless of the nature of the thrombotic event, gender, APS category and age at APS onset.References[1]GRIKA EP, ZIAKAS PD, ZINTZARAS E, MOUTSOPOULOS HM, VLACHOYIANNOPOULOS PG: Morbidity, Mortality, and Organ Damage in Patients with Antiphospholipid Syndrome. J Rheumatol. 2012;39(3):516–23.[2]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.Disclosure of InterestsPedro Gaspar: None declared, Filipa Farinha: None declared, Zara Sayar: None declared, Maria Efthymiou: None declared, Hannah Cohen Speakers bureau: Honoraria for lectures from Bayer Healthcare (outside the submitted work)., Consultant of: Consultancy fees from UCB Biopharma paid to University College London Hospitals Charity (outside the submitted work)., David Isenberg: None declared

NEW FINDINGS What is the central question of this study? Angiotensin-(1-7) decreases cerebral infarct volume and improves neurological function when delivered centrally before and during ischaemic stroke. Here, we assessed the neuroprotective effects of angiotensin-(1-7) when delivered orally post-stroke. What is the main finding and its importance? We show that oral delivery of angiotensin-(1-7) attenuates cerebral damage induced by middle cerebral artery occlusion in rats, without affecting blood pressure or cerebral blood flow. Importantly, these treatments begin post-stroke at times coincident with the treatment window for tissue plasminogen activator, providing supporting evidence for clinical translation of this new therapeutic strategy. ABSTRACT As a target for stroke therapies, the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas [ACE2/Ang-(1-7)/Mas] axis of the renin-angiotensin system can be activated chronically to induce neuroprotective effects, in opposition to the deleterious effects of angiotensin II via its type 1 receptor. However, more clinically relevant treatment protocols with Ang-(1-7) that involve its systemic administration beginning after the onset of ischaemia have not been tested. In this study, we tested systemic post-stroke treatments using a molecule where Ang-(1-7) is included within hydroxypropyl-β-cyclodextrin [HPβCD-Ang-(1-7)] as an orally bioavailable treatment. In three separate protocols, HPβCD-Ang-(1-7) was administered orally to Sprague-Dawley rats after induction of ischaemic stroke by endothelin-1-induced middle cerebral artery occlusion: (i) to assess its effects on cerebral damage and behavioural deficits; (ii) to determine its effects on cardiovascular parameters; and (iii) to determine whether it altered cerebral blood flow. The results indicate that post-stroke oral administration of HPβCD-Ang-(1-7) resulted in 25% reductions in cerebral infarct volumes and improvement in neurological functions (P

Significant neuroprotective effects of angiotensin II type 2 (AT 2 ) receptor (AT 2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT 2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT 2 receptor agonist Compound 21 (C21) to näive rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT 2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT 2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

Background:Patients with systemic lupus erythematosus (SLE) who received anifrolumab, a type I interferon receptor antibody, had greater BILAG–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week (W)52 in the phase 2 MUSE1 and the phase 3 TULIP-12 and TULIP-23 trials. Patients receiving anifrolumab also had fewer flares, and more patients were able to taper glucocorticoids (GC) vs placebo.1–3Objectives:To evaluate anifrolumab treatment response vs placebo in patients with SLE from MUSE, TULIP-1, and TULIP-2 using more stringent BICLA definitions, as well as a novel endpoint that requires dual BICLA and SLE Responder Index (SRI[4]) responses.Methods:MUSE (NCT01438489), TULIP-1 (NCT02446912), and TULIP-2 (NCT02446899) were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks) in patients with moderate to severe SLE despite standard therapy.1–3 Sustained GC taper was defined as taper to ≤7.5 mg/day in patients receiving GC ≥10 mg/day at baseline, or to less than or equal to baseline dose in patients receiving GC 1) attained a W52 BICLA response with sustained GC taper; 2) attained a W52 BICLA response and no flares after W12 (flare defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores vs the prior visit); 3) attained a W52 BICLA response with sustained GC taper and no flares after W12; 4) attained an enhanced BICLA (eBICLA) response at W52 that required complete resolution of all baseline BILAG-2004 activity (all baseline A/B scores to D; no worsening of C or D scores); and 5) met both BICLA and SRI(4) response criteria.Results:Evaluated patients received anifrolumab 300 mg (MUSE, n=99; TULIP-1 and TULIP-2, n=180) or placebo (MUSE, n=102; TULIP-1, n=184; TULIP-2, n=182). Response rate differences favoring anifrolumab 300 mg over placebo were observed for all 5 endpoints across MUSE, TULIP-1, and TULIP-2 (Figure 1). A greater proportion of patients had BICLA responses at W52 with sustained GC taper with anifrolumab vs placebo. More patients had BICLA responses at W52 with no flares after W12 with anifrolumab vs placebo. More patients had BICLA responses at W52 with both sustained GC taper and no flares after W12 with anifrolumab vs placebo (treatment difference, 15.3%–19.3%; nominal P≤0.006). More patients attained eBICLA responses (requiring complete resolution of baseline disease activity) at W52 with anifrolumab vs placebo (treatment difference, 11.1%–14.1%; nominal P≤0.017). In addition, more patients were dual BICLA and SRI(4) responders at W52 with anifrolumab vs placebo (treatment difference, 14.3%–28.6%; nominal P≤0.004).Conclusion:In phase 2 and 3 trials in patients with SLE, anifrolumab treatment was consistently associated with improved disease control vs placebo using stringent endpoint definitions, including BICLA response with sustained GC taper and no flares, an enhanced BICLA response requiring complete resolution of baseline disease activity, and dual BICLA and SRI(4) responses.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Rosie Butler, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:David Isenberg Consultant of: AstraZeneca, Celgene, Merck Serono, UCB, and Servier, Ian N. Bruce Speakers bureau: AstraZeneca, GSK, and UCB, Consultant of: Eli Lilly, GSK, ILTOO, Merck Serono, and UCB, Grant/research support from: Genzyme/Sanofi, GSK, Roche, and UCB, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, and YL Biologics, Grant/research support from: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Takeda, and UCB, Susan Manzi Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Kenneth Kalunian Consultant of: AstraZeneca, Konstantina Psachoulia Employee of: AstraZeneca, Emmanuelle Maho Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

Background:There had been very limited data on the development of damage and mortality in an inception cohort of SLE patients who were recruited very soon after diagnosis.Objectives:This study aimed to analyse the development of damage and death in an inception cohort of SLE patients recruited within 1 year of diagnosis with up to 13 years of follow-up.Methods:This was a prospective multi-centre longitudinal study in the UK of SLE patients recruited within 12 months of achieving 1997 ACR revised criteria for SLE. Data were collected on BILAG-2004, BILAG2004-Pregnancy Index (during pregnancy), SLICC/ACR DI (SDI), cumulative drug exposure and death at every visit. Information on cardiovascular risk factors and antiphospholipid syndrome status were also collected. This study ran from 1st January 2005 to 31st December 2017. Mortality and development of damage were analysed.Results:There were 273 patients recruited (91.2% female, 59.3% Caucasian, 17.2% African/Caribbean, 17.2% South Asian) with mean age at recruitment of 38.5 years (SD 14.8). 97.8% had no damage at recruitment (2.2% had SDI score of 1). Median follow-up was 73.4 months (range: 1.8, 153.8) with total follow-up of 1767 patient-years.There were 13 deaths (4.8%): 76.9% female, 84.6% Caucasian, 15.4% South Asian, mean age 62.6 years (± SD 15.8) and mean disease duration 3 years (± SD 1.8). Causes of death were cancer in 5 (38.5%), infection in 3 (23.1%), ischaemic heart disease in 1 (7.7%) and unknown in 4 (30.8%).114 new damage items in 83 patients occurred during follow-up. The distribution of damage was musculoskeletal (21, 18.4%), ophthalmic (18, 15.8%), neuropsychiatric (18, 15.8%), renal (14, 12.3%), malignancy (12, 10.5%), cutaneous (7, 6.1%), GIT (7, 6.1%), cardiac (6, 5.3%), pulmonary (4, 3.5%), diabetes mellitus (4, 3.5%) and vascular (3, 2.6%). The rate of development of damage appears to be higher in the first 3 years which subsequently stabilised (Table 1).Table 1.Incidence rate of development of damage over period of follow-up at 3 yearly intervalsPeriod of follow-up (year)Person-years at riskNumber of new items of damageIncidence rate, per 1000 person-years (95% CI)0 – 3753.46079.6 (61.8, 102.6)3 – 6534.03158.1 (40.8, 82.6)6 – 9321.21237.4 (21.2, 35.8)9 – 12152.5532.8 (13.6, 78.7)> 125.90-Conclusion:Mortality is uncommon during the first 12 years of follow-up for newly diagnosed SLE patients. However, development of damage appears to be higher in the first 3 years before stabilizing to a lower rate subsequently.Acknowledgements:Versus Arthritis, VIfor PharmaDisclosure of Interests:Chee-Seng Yee Consultant of: Bristol Myer Squibb, ImmuPharma, Grant/research support from: Vifor Pharma, Vernon Farewell: None declared, Mohammed Akil: None declared, Peter Lanyon: None declared, Christopher John Edwards Consultant of: Glaxo Smith Kline, Roche, Grant/research support from: Glaxo Smith Kline, Roche, David Isenberg: None declared, Anisur Rahman: None declared, Lee-Suan Teh: None declared, Sofia Tosounidou: None declared, Robert Stevens: None declared, Ahtiveer Prabu: None declared, Bridget Griffiths: None declared, Neil McHugh: None declared, Ian N. Bruce: None declared, Yasmeen Ahmad: None declared, Munther Khamashta: None declared, Caroline Gordon Speakers bureau: UCB, Consultant of: Center for Disease Control, Astra-Zeneca, MGP, Sanofi and UCB

Background: Compound 21 (C21), a selective small-molecule angiotensin type 2 receptor (AT2R) agonist, has been proven in multiple preclinical studies to reduce infarct size and ameliorate neurological deficits, when administered after ischemic stroke via intracerebroventricular or intraperitoneal routes. However, C21 poorly penetrates the blood brain barrier (BBB). In this study, we used the novel and non-invasive approach of intranasal trans-olfactory (INTO) application, in order to bypass the BBB and deliver C21 directly into the brain. The therapeutic efficacy of INTO application of C21 was assessed in a model of transient middle cerebral artery occlusion (MCAO). Methods: (i) Male SD rats (12 weeks old) underwent ischemic stroke by endothelin-1-induced MCAO. They were randomly divided into two treatment groups, either receiving 0.9% saline or C21 (1.5 ug/kg) at 1.5, 4, 24 and 48 h post-stroke, using a rat intranasal catheter device (Impel Neuropharma, Seattle, WA) for INTO application. All rats underwent blinded neurological assessments at 4, 24 and 72 h after stroke, and immediately after the 72 h tests, were euthanized and cerebral infarct volumes were assessed by TTC staining. (ii) Male SD rats (12 weeks old) underwent implantation of a telemetry transducer (DSI, St. Paul, MN) into the abdominal aorta for measurement of blood pressure, heart rate and locomotor activity after INTO C21 (1.5 ug/kg) vs. 0.9% saline at baseline and post-ischemic stroke. Results: (i) Post-stroke INTO delivery of C21 (1.5 ug/kg) elicited a significant lowering of % cerebral infarct volume (25.4 ± 4.7; n=9) compared with saline-treated rats (48.4 ± 4.4; n=21) [p Conclusions: Our results demonstrate, that INTO delivery of C21 exerts protective effects after ischemic stroke. These studies suggest INTO administration as potential future route of application of C21 to stroke patients.

Purpose: The Medical Outcome Survey Short Form 36 (SF-36) is recommended to assess quality of life (QoL) in SLE. The aim of the current study was to assess QoL over time in the first 5 years of a multi-centered inception cohort of patients with SLE.. Methods: An inception SLE cohort has been assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had at least 5 completed QoL questionnaires were included in these analyses. GEE models were run separately for each of the 8 subscales and for the physical and mental component summary scores (PCS and MCS), adjusting for repeated measures by patients. Results: 495 patients were included. The mean (� SD) disease duration at first visit was 5.3� 4.1 months. The mean age at enrolment was 35.8 � 13.2 years. All 8 subscales and 2 summary scores showed improvement in the first 2 years from enrolment. Between years 2 and 5 none of the subscales or summary scores showed any change. Minimal clinically important improvement was achieved by 35-55% of the patients and was influenced by demographic and disease factors. Conclusion: Unlike late stage lupus where QoL is stable over time, in patients with early disease all subscales improve in early follow-up up to 2 years. Therefore the SF-36 may be a sensitive outcome measure in early disease in patients with SLE. � 2014 American College of Rheumatology.

Background: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2Rs). Compound 21 (C21), a selective non-peptide AT2R agonist, has been shown to exhibit neuroprotection and improve stroke outcomes in preclinical studies. Stimulation of AT2Rs is believed to counteract the negative effects of angiotensin type 1 receptor and provide distinctive beneficial anti-inflammatory and neurotropic effects. We hypothesized that C21 given after stroke through peripheral injections would have sustained neuroprotective effects in aged rats. Methods: Aged adult male SD rats (18-20 months) underwent ischemic stroke by monofilament middle cerebral artery occlusion (MCAO) and were randomly divided into two groups that received intraperitoneal (IP) injections of either 0.9% NaCl or 0.03mg/kg C21 at reperfusion (90 min), 24h, and 48h after stroke. All animals received blinded neurological exams at 4h, 24h, 72h, 7d, 14d, and 21d post-stroke. Infarct size was assessed by magnetic resonance imaging at 21 days. Results: Post-stroke treatment with C21 significantly improved neurological function, as evidenced by neurological testing using Rotarod and somatosensory dysfunction exams. At 7d and 14d after stroke, C21-treated rats had significantly increased Rotarod times versus saline-treated rats, and at 21d, the somatosensory function was significantly improved as measured by time to removal of paw adhesive. Infarct volume tended to be non-significantly decreased by C21 treatment at 21d post-stroke. Conclusions: Our findings indicate that targeting the renin-angiotensin system, specifically by stimulation of AT2Rs with C21, improves neurological function in aged rats with stroke over a sustained period of 21 days. These findings encourage further research into the renin-angiotensin system and specifically AT2Rs, and offers hope for effective alternatives for treating stroke.

To describe the clinical outcome and safety of rituximab (RTX) treatment in systemic lupus erythematosus (SLE) patients with severe manifestations or whose disease is refractory to standard immunosuppressive therapy, treated at a single center.This was a retrospective analysis of all patients with SLE treated with RTX at 1 center between June 2000 and December 2013. The clinical outcome was assessed by determining British Isles Lupus Assessment Group (BILAG) scores and anti-double-stranded DNA (anti-dsDNA) and C3 levels before and 6 months after RTX treatment. For safety analysis, adverse events and deaths were recorded.Of a total of 115 patients, 93.9% were female, the mean ± SD age at diagnosis was 26.39 ± 11.90 years, and the mean ± SD disease duration at first RTX treatment was 91.96 ± 84.80 months. A BILAG score variation of -11.26 ± 11.38 (P 0.001) was recorded 6 months after the first RTX treatment; 40% of patients had a complete response and 27% had a partial response; in 36.5% of patients, C3 levels increased more than 25%, and in 33.5% anti-dsDNA levels decreased more than 50%. Depletion of CD19+ cells was achieved in 94.0% of patients. Hypogammaglobulinemia was detected in 14.9% of patients, with significant reduction for IgM (P 0.001) and IgG (P = 0.001) levels. Severe infections, infusion-related reactions, and hypersensitivity reactions occurred in 7%, 3.5%, and 2.6% of patients, respectively. Of the 115 patients, 62 patients had repeated RTX treatments, with an average number of 1.95 ± 1.17 cycles per patient and a mean ± SD interval between infusions of 21.44 ± 20.11 months. At the end of followup, 11 patients were deceased; 6 had cardiovascular events.RTX treatment was effective in decreasing disease activity, with a low incidence of adverse effects.

ObjectiveNeuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events.MethodsPatients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression.ResultsDisease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events.ConclusionIn a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

OBJECTIVES: To develop models for disease activity in patients with systemic lupus erythematosus (SLE) and to examine the hypothesis that possible subsets exist within the disease, notably renal disease and little else, mucocutaneous and musculoskeletal disease in isolation and more multisystem disease. METHODS: Four hundred and forty patients with SLE were followed for a period of 10 yr. Socio-demographic data were obtained at the first visit with disease activity being recorded at subsequent visits and damage scores at 6-monthly intervals. Prognostic factors for active disease in each of the mucocutaneous, musculoskeletal and renal systems were examined statistically. The results were then validated using data collected over 5 yr on a further 295 SLE patients from a different centre. RESULTS: Logistic regression analyses indicated that for all three systems studied a patient known to have an involvement in that system is more likely to present with active disease in that same system than a patient with no known prior involvement. Patients with a higher frequency of clinic visits with active disease in a system are more likely to represent with active disease than those with fewer visits. The results suggest that renal disease is most likely to occur on its own. Associations between activity in the mucocutaneous and musculoskeletal systems support the suggestion that patients with musculoskeletal and mucocutaneous disease alone represent a possible subset of SLE. None of the associations identified were modified by the medication a patient received. CONCLUSIONS: Previous disease history and involvement of other systems determine a patient's chance of developing further episodes of active disease in SLE.

Chlamydia trachomatis is the leading cause of sexually transmitted disease in the United States. Effective screening for this agent can facilitate prompt treatment and prevent its sequelae. The recent introduction of liquid-based cytology has made possible the simultaneous screening of cervical intraepithelial lesions and detection of C. trachomatis in a single collection vial. In this study we determined whether cytological fluid could support DNA-based amplification for the detection of C. trachomatis . Three methods were compared, including ramification amplification (RAM), real-time PCR with molecular beacon, and Abbott’s ligase chain reaction (LCx). RAM is a novel, recently introduced, isothermal DNA amplification technique that utilizes a circular probe for target detection and achieves exponential amplification through the mechanism of primer extension, strand displacement, and ramification. Our results show that RAM can detect as few as 10 C. trachomatis elementary bodies in less than 2 h, comparable to results with real-time PCR. Thirty clinical specimens collected in PreservCyt solution were tested by LCx, real-time PCR, and RAM. Among 30 specimens, 15 were positive by PCR and LCx and 14 were positive by RAM. One specimen missed by RAM had an inadequate amount of residual cellular material. Our results show that nucleic acid amplification methods can serve to detect C. trachomatis and presumably other sexually transmitted agents in cytological fluid and that the RAM assay can be an alternative to PCR and LCx because of its simplicity and isothermal amplification.

Objective To determine the prevalence of traditional cardiovascular risk factors using established definitions in a large cohort of clinically well-characterized primary Sjögren's syndrome (SS) patients and to compare them to healthy controls. Methods Data on cardiovascular risk factors in primary SS patients and controls were collected prospectively using a standardized pro forma. Cardiovascular risk factors were defined according to established definitions. The prevalence of cardiovascular risk factors in the primary SS group was determined and compared to that in the control group. Results Primary SS patients had a higher prevalence of hypertension (28–50% versus 15.5–25.6%; P < 0.01) and hypertriglyceridemia (21% versus 9.5%; P = 0.002) than age- and sex-matched healthy controls. Furthermore, a significant percentage (56%) of hypertensive patients expected to be on antihypertensive treatment according to best practice was not receiving it. Conclusion Primary SS patients are more than 2 times more likely to experience hypertension and hypertriglyceridemia than age- and sex-matched healthy controls. Additionally, hypertension is underdiagnosed and suboptimally treated in primary SS.

Necrotising fasciitis (NF) is a rare infection of the subcutaneous tissue, known to be rapidly progressive and potentially fatal. Patients with systemic lupus erythematosus (SLE) may be predisposed to this condition, and early clinical recognition can be difficult. We report a case of necrotising fasciitis in a 26-year-old woman with SLE. She presented with painful swelling of her left leg, then developed clinical features of septic shock. Emergency debridement was performed. Intraoperative findings revealed NF and cultures grew Pseudomonas aeruginosa. The patient survived after a lengthy hospital admission, following several further debridements complicated by recurrent chest sepsis and multiorgan failure. We also review and discuss the published cases of NF in SLE patients.

A standard electrode surgical generator connected to a Nitinol coil was used in vitro to evaluate whether the generated electromagnetic energy had any bactericidal effect on Escherichia coli.The ATCC 259222 E. coli strain was used. We mixed 135 mL of a 1.5% non-nutritive agar with 15 mL of a 10(6) CFU/mL inoculum and transferred it to gas-sterilized plastic containers lined with aluminium foil. A 22F cylindrical shape was cut from the center of the agar, and a Nitinol coil was placed in that space and connected to a standard electrode surgical generator. Electrical energy was then applied from 5 to 25 V at 5-V increments. Temperatures were measured with two thermocouples placed in the middle and periphery of each agar. The treatment was stopped when the temperature at the middle thermometer reached 50 degrees C. The control group was not treated and was embedded in a water bath at 45 degrees C. Three 3 x 7-mm pieces were sliced from the inner to the outer part of the agar and processed, and colony counts were performed.We observed statistically significant deleterious effects on E. coli in all three zones when the treatment voltage was 15 and 20. When the potential was raised to 25 V, we observed a significant result only in the core zone. The treatment duration was 50 minutes for 5 and 10 V, 45 minutes for 15 V, 15 minutes for 20 V, and 10 minutes for 25 V.The bactericidal effect was mainly in the central area, decreasing linearly toward the periphery, and was related to the temperature reached during activation of the electrical generator. These results were disappointing with regard to the utility of Nitinol stents to treat bacterial prostatitis.

Objectives. We investigated the in vitro nonthermal effects of microwaves delivered from Prostatron 2.0 on Escherichia coli and Enterobacter cloacae . Methods. The fingers of powder-free, sterile gloves were ligated, and bacterial solutions were transferred into the remaining area of the glove. The gloves were then sealed using silk ligatures. One set of gloves was subjected to the microwave treatment while another set was placed in a temperature-matched waterbath to act as control samples. The gloves containing the treatment group were taped around the probe, at the site where microwave energy exits the probe. During the treatment period, the temperatures from the urethral probe and the rectal probe were carefully monitored. Results. The mean (±SD) energy delivered was 46.6 ± 9.5 kJ (range 30.0 to 59.5) for the 10 trials on E. coli and colony counts in the experimental microwaved gloves decreased significantly compared with control samples (5.26 ± 4.5 × 10 5 versus 10.16 ± 9.3 × 10 5 CFU/mL, P = 0.02). For the experiments on E. cloacae the mean (±SD) energy applied was 38.5 ± 12.5 kJ, and a significant decrease in colony counts of microwaved samples was also observed compared with controls (11.04 ± 4.8 × 10 5 versus 20.08 ± 10.1 × 10 5 CFU/mL, P = 0.004). Conclusions. Microwave energy, delivered from Prostatron 2.0, independent of heat production has an in vitro bactericidal effect on laboratory-cultured E. coli and E. cloacae .

With the goal of making high-sensitivity bolometers for low-background measurements in the far-infrared or submillimeter, we have made small silicon thermistors, which act as hot-electron bolometers, with integrated single-electron transistors for readout amplifiers. Semiconductors doped just below a metal–insulator transition can make highly sensitive thermistors that have been used as thermometers in X-ray microcalorimeters and FIR bolometer arrays. In such arrays, thermal isolation is engineered by supporting the absorber and thermometer on a membrane. However, electron–phonon decoupling in doped silicon can be made the dominant thermal isolation by reducing device volume, potentially allowing a smaller thermal conductance and a more sensitive bolometer. A key feature is that, while its DC resistance is very high, the thermistor's surface impedance at terahertz frequencies is conveniently low, making feasible efficient antenna coupling of radiation into the electron system. Radio-frequency single-electron transistors integrated with the thermistors have sufficiently low input capacitance to offer high-speed readout of the high impedance detectors.

Background: The incidence of vancomycin-resistant enterococci (VRE) has reached endemic proportions in many medical centers. To initiate an effective infection control program, an understanding of the epidemiologic attributes of the genus in medical facilities is imperative. Methods: We studied 138 consecutive cases of VRE from April through December 1995. We created a database to analyze the risk factors for patients in both an adult hospital and a children's hospital and screened all specimens, submitted for routine microbiologic analysis, for VRE. Results: One hundred twenty-three cases (89%) occurred in the adult acute care hospital, and 15 (11%) occurred in the children's hospital. Eight patients (58%) were colonized with VRE, and 58 (42%) had an infection with VRE. Eighty-three percent of all the cases of VRE were nosocomially acquired. The majority of cases occurred in the medical service. Urine was the most important clinical specimen infected or colonized. Prior use of an antibiotic, other than vancomycin, was the most important risk factor for all nosocomial cases, followed by prior vancomycin use for surgical patients and residence in a unit with other patients infected with VRE for the medical service. Direct admission from another hospital was the most important risk factor for community-acquired cases. Special microbiologic screening of cultures yielded 48% of all VRE identified. Enterococcus faecium was the predominant resistant isolate recovered. Conclusions: The control of VRE in the hospital setting is difficult for several reasons. Almost half of all patients carrying VRE would not have been identified without special microbiologic screening efforts, as would patients, admitted from the community, who are already colonized with VRE. Controlling antibiotic use both in the hospital and the community is basic for controlling these organisms. Continuous education of all staff about VRE and other nosocomially significant organisms is the key to controlling the spread of these bacteria.

Two studies are presented that investigate the developmental aspect of visual‐motor integration by children with Williams syndrome and normally developing children. In Study 1, drawings by 9‐ and 10‐year‐olds with Williams syndrome were compared to drawings by 2 groups of normally developing children: 1 group individually matched for chronological age and another group individually matched for mental age. In Study 2, the normal developmental course for this spatial cognitive skill was examined for 40 normally developing children ages 4 years to 7 years. In both studies, 2 drawing tasks were used: the Short Form of the Developmental Test of Visual Motor Integration (VMI) and drawing then copying a flower, house, and elephant from the Boston Diagnostic Aphasia Evaluation (BDAE). Results from Study 1 indicated that, as expected, the children with Williams syndrome scored significantly lower on the VMI and produced significantly fewer recognizable drawings than did either their chronological age matches or th...