Faculty Bibliography

OBJECTIVES: The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). METHODS: 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. RESULTS: Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. CONCLUSIONS: Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. TRIAL REGISTRATION NUMBER: NCT01283139; Results.

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: 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: We previously reported that lupus anticoagulant (LAC) is the main predictor of poor pregnancy outcome in antiphospholipid antibody (aPL)-positive patients. We sought to confirm this finding in an independent group of patients who were subsequently recruited into the PROMISSE study. METHODS: The PROMISSE study is a multicentre, prospective, observational study of pregnancy outcomes in women with aPL and/or systemic lupus erythematosus (SLE) that enrolled patients from 2003 to 2015. All consecutive, aPL-positive patients from the PROMISSE study who completed their pregnancy between April 2011 and January 2015 (after the previous PROMISSE report) are included in the current report. Patients were followed monthly until delivery, and aPL was tested at first, second and third trimesters of pregnancy and at 12 weeks post partum. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation, neonatal death, delivery prior to 36 weeks of gestation due to pre-eclampsia or placental insufficiency or small-for-gestational age (birth weight <5th percentile). RESULTS: Forty-four aPL-positive patients are included in this paper. Thirteen patients had APOs, which occurred in 80% of cases during the second trimester of pregnancy. LAC was present in 69% of patients with APOs compared with 27% of patients without APOs (p=0.01). No association was found between anticardiolipin antibodies (aCL) or anti-beta2 glycoprotein I antibodies (abeta2GPI) IgG or IgM positivity and APOs. Definite antiphospholipid syndrome (history of thrombosis and/or pregnancy morbidity and aPL) was found in 92% of patients with any APOs compared with 45% of patients without APOs (p=0.004). Conversely, the frequency of SLE was not statistically different between those with and without APOs (30% vs 39%). CONCLUSIONS: Our findings, in an independent group of aPL-positive patients from the PROMISSE study, confirm that LAC, but not aCL and abeta2GPI, is predictive of poor pregnancy outcomes after 12 weeks of pregnancy. TRIAL REGISTRATION NUMBER: NCT00198068.

BACKGROUND: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high risk population. In non-autoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. OBJECTIVE: To determine whether early dysregulation of circulating angiogenic factors, can predict APO in high risk SLE and/or APL pregnancies. STUDY DESIGN: We used data and samples from the PROMISSE Study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus), a multi-center prospective study that enrolled 492 pregnant women with SLE and/or APL between September 2003 and August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured monthly and subjects followed for APO, classified as severe (PE<34 weeks, fetal/neonatal death, indicated pre-term delivery <30 weeks) or moderate (PE>/=34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). RESULTS: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and sEng levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio=17.3 comparing highest and lowest quartiles, 95% CI: 3.5-84.8; positive predictive value (PPV)=61%; negative predictive value (NPV)=93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/ml) and sFlt1 in highest quartile (>1872 pg/ml; odds ratio=31.1; 95% CI: 8.0-121.9; PPV=58%; NPV=95%). Severe APO rate in this high risk subgroup was 94% (95%CI: 70%-99.8%), if lupus anticoagulant or history of high blood pressure is additionally present. In contrast, among patients with both sFlt1 <1872 pg/ml and PlGF >70.3 pg/ml, rate of severe APO was only 4.6% (95% CI: 2.1%- 8.6%). CONCLUSIONS: Circulating angiogenic factors measured during early gestation have a high negative predictive value in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of healthcare resources.

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 (