Faculty Bibliography

Background Anifrolumab was evaluated in a Phase IIb study ofadults with moderate to severe systemic lupus erythematosus(SLE), in which 305 patients received intravenous infusions ofanifrolumab (300 mg, 1000 mg) or placebo for 48 weeks. Globaldisease activity was reduced in both dose groups compared withplacebo, although a more favourable risk-benefit profile wasobserved with the 300-mg dose. This analysis of the Phase IIbstudy compared the impact of anifrolumab on individual organdomains in patients.Materials and methods Changes from baseline in organ domainactivity were assessed at Week 52 using the SLE Disease ActivityIndex 2000 (SLEDAI-2K) and British Isles Lupus AssessmentGroup (BILAG). SLEDAI domain improvement required a lowerscore compared with baseline in at least one of its components.BILAG organ domain improvement was defined as the transitioning from A or B to a lower score.Results The majority of patients had baseline involvement of themucocutaneous and/or musculoskeletal domains of SLEDAI-2Kand BILAG. A greater percentage of anifrolumab-treated patientsdemonstrated improvement in these frequently involved domainscompared with placebo (Table 1). Potential benefits were observedin most of the other less frequently active domains, including SLEDAI-2K cardiorespiratory, vascular, haematological, and constitutional; and BILAG cardiorespiratory and constitutional domains.In patients with baseline involvement in the SLEDAI-2K immunological domain (positive anti-double-stranded DNA [anti-dsDNA]and/or low complement level), normalisation of anti-dsDNA and/or hypocomplementemia were seen more frequently at Day 365 inpatients receiving anifrolumab compared with placebo (Table 1).However, among patients who had a normal anti-dsDNA and/ornormal complements at baseline, a slightly greater number ofpatients in the 300-mg anifrolumab group had an increase in thescore representing the development of a new anti-dsDNA or hypocomplementemia compared with baseline (Table 1).Conclusions Treatment with anifrolumab resulted in greaterrates of improvement in multiple organ domains compared withplacebo. The greatest impact was seen with 300-mg anifrolumab

Background When found in the absence of antibodies toextractable nuclear antigens (ENA) or anti-double-stranded DNA(dsDNA) (i.e., monospecific), autoantibodies to the nuclear autoantigen dense fine speckles 70 (DFS70) are purported to ruleout SLE. The reported frequency of anti-DFS70 by chemiluminescence (CIA) in SLE is low compared to healthy individuals(0-5.7% vs. 1.3-23.2%), while the frequency of monospecificanti-DFS70 in SLE is even lower at 0-0.4%. There are no studies examining the frequency of anti-DFS70 in an early inceptionSLE cohort. This study determined the prevalence of antiDFS70 in a multi-national, multi-ethnic early inception SLEcohort and examined demographic, clinical, and autoantibodyassociations.Materials and methods Patients fulfilling ACR Classification Criteria for SLE were enrolled in the Systemic Lupus InternationalCollaborating Clinics (SLICC) inception cohort within 15months of diagnosis. Demographic and clinical data were collected at enrollment. ANAs were detected by indirect immunofluorescence on HEp-2 cells (ImmunoConcepts, Sacramento)and ENAs and dsDNA by an addressable laser bead immunoassay (FIDIS Connective13, TheraDiag, Paris). Anti-DFS70 antibodies were measured by CIA (Inova Diagnostics, San Diego).The association between anti-DFS70 and baseline demographic,clinical, and autoantibody profiles was assessed using univariateand multivariate logistic regression. For the most informativemodel, only the remaining statistically significant predictors atthe 95% CI: were included, after eliminating other potentialpredictors individually, starting with the least likely to be associated with the outcome.Results 1137 patients were included; 89.9% were female and93.8% were ANA positive (Table 1). The frequency of antiDFS70 was 7.1% [95% CI: 5.7-8.8%]. 13 of 1137 (1.1%)[95% CI: 0.6-1.9%] were positive for anti-DFS70 only (monospecific). In univariate analysis, patients with musculoskeletalactivity (based on SLEDAI items) or anti-b-2 glycoprotein-1(anti-b2GP1) were more likely to have anti-DFS70, whereasthose with anti-dsDNA, anti-SSA/Ro60, anti-SSB/La, or antiU1RNP were less likely to have anti-DFS70. In multivariateanalysis, patients with musculoskeletal activity (Odd Ratio (OR)1.25 [95% CI: 1.10, 1.41]) or anti-b2GP1 (OR 2.15, 95% CI:1.21, 3.84) were more likely to have anti-DFS70, while thosewith anti-dsDNA (OR 0.53, 95% CI: 0.31, 0.92) or anti-SSB/La(OR 0.25, 95% CI:0.08, 0.82) were less likely to have antiDFS70.Conclusions The prevalence of anti-DFS70 in newly diagnosedSLE patients was at the high end of the range previouslypublished for SLE (7.1% vs. 0-5.7%) and was associated withmusculoskeletal activity and anti-b2GP1. However, 'monospecific' anti-DFS70 was rare (1.1%) and is potentially useful to discriminate between ANA positive healthy individuals and SLE

OBJECTIVE:Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. METHODS:A total of 74 lupus patients with an SLE Disease Activity Index score of 0-18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. RESULTS:We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA-26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. CONCLUSION:An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non-Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.

OBJECTIVE: To measure antiphospholipid antibody (aPL) variance during pregnancy; to determine if variation affects outcomes. METHODS: We used data from PROMISSE, a multicenter prospective study of pregnant women with aPL and/or SLE. APL was present if any of the following was positive: anticardiolipin (aCL), anti-beta2glycoprotein I (abeta2GPI) titers >/=40 GPL or MPL units, and/or lupus anticoagulant (LAC). APL were measured every trimester and post-partum. Adverse pregnancy outcomes (APOs) were defined as: fetal/neonatal death, preterm delivery <36 weeks due to preeclampsia or placental insufficiency; or growth restriction. RESULTS: One hundred and fifty-two aPL-positive patients were studied: 57% with clinical APS and 36% with SLE. aPL IgG levels were significantly lower during 2nd and 3rd trimesters compared to screening, but IgG aCL and abeta2GPI remained high-positive through pregnancy in 93% and 85% of patients, respectively. APL IgM titers were negative in the majority of patients and fell modestly during pregnancy. LAC frequency also decreased, but 75% remained positive through the 2nd trimester. Only 4% of patients with aPL at baseline did not have aPL at either 2nd or 3rd trimester. Changes in aPL levels or aPL status were not associated with APOs. LAC was the only aPL associated with APOs. CONCLUSION: APL levels decreased marginally during pregnancy, and changes were not associated with pregnancy outcome. Our findings suggest that measurement of aPL early is sufficient to assess risk . Repeat aPL testing through pregnancy is unnecessary

OBJECTIVE: To study bidirectional change and predictors of change in estimated glomerular filtration rate (eGFR) and proteinuria (ePrU) in lupus nephritis (LN) using a multistate modelling approach. METHODS: In the SLICC inception cohort we determined annual eGFR state 1 (eGFR: >60 ml/min), 2 (eGFR: 30-60 mL/min), and 3 (eGFR: <30 ml/min); ePrU state 1 (ePrU: <0.25 gr/day), 2 (ePrU: 0.25-3.0 gr/day), and 3 (ePrU: >3.0 gr/day); End stage renal disease (ESRD) and death. Using multistate modelling, relative transition rates between states indicated improvement and deterioration. RESULTS: In 700/1,826 (38.3%) patients with LN, and mean (SD followup 5.2(3.5) years the likelihood of improvement in eGFR and ePrU was greater than deterioration. After 5 years, estimated transition to ESRD was 62% of patients initially in eGFR state 3 and 11% from ePrU state 3. The probability of remaining in initial eGFR states 1, 2 and 3 was 85%, 11%, 3% and for ePrU was 62%, 29%, 4%. Male sex predicted improvement in eGFR states; older age, race/ethnicity, higher ePrU state and higher renal biopsy chronicity scores predicted deterioration. For ePrU, race/ethnicity, earlier calendar years, damage scores without renal variables and higher renal biopsy chronicity scores predicted deterioration; male sex, positive lupus anticoagulant, class V nephritis and mycophenolic acid use predicted less improvement. CONCLUSION: In LN, the expected improvement and deterioration in renal outcomes can be estimated by multistate modelling and is predicated by identifiable risk factors. New therapeutic interventions for LN should meet or exceed these expectations

OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in approximately 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was approximately 2.5 and approximately 2.9 times higher, respectively, than that in women with 46,XX and approximately 25 and approximately 41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

OBJECTIVE:The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). METHODS:Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. RESULTS:A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. CONCLUSION/CONCLUSIONS:Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

OBJECTIVE: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. METHODS: Patients in the Systemic Lupus International Collaborating Clinics inception cohort (