Faculty Bibliography

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.

Background/Purpose: The efficacy and safety of anifrolumab (ANIFR), a type I IFN receptor antagonist, were assessed in a Phase II, randomized, double-blind, placebo-controlled study in SLE (NCT01438489). Methods: Three hundred and five adults with seropositive moderate to severe SLE despite standard of care medication were randomized and received intravenous (iv) ANIFR (300 mg, 1000 mg) or placebo (PBO) every 4 weeks for 48 weeks. Patients were stratified by SLEDAI score, oral corticosteroid (OCS) dose, and IFN gene signature (IFN high vs. IFN low) based on a 4-gene expression assay. Disease activity was assessed by SLEDAI-2K, BILAG 2004, Physician's Global Assessment, CLASI, BICLA, and 28-joint count. The primary endpoint was a composite of SRI(4) response at Day 169 with sustained reduction of OCS (<10 mg/day and 10 mg/day at baseline. Other efficacy measures of systemic and organ-specific disease activity and safety were also assessed at Day 365. Results: The primary endpoint at Day 169 was met by a greater proportion of ANIFR-treated patients vs. PBO (PBO: 17.6%; 300 mg: 34.3%, p=0.014; 1000 mg: 28.8%, p=0.063). At Day 365, the secondary SRI endpoint was met by 25.5% of PBO, 51.5% of 300 mg (p<0.001) and 38.5% of 1000 mg (p=0.048) patients. OCS reduction to <7.5 mg/day at Day 365 was achieved by 26.6% of PBO, 56.4% of 300 mg (p=0.001) and 31.7% of 1000 mg (p=0.595) patients. ANIFR demonstrated consistent benefit across multiple global and organ-specific measures at Day 365 (Table), as well as lower rates of BILAG moderate/severe flares/patient-year (PBO: 0.611; 300 mg: 0.266; 1000 mg: 0.391). 75% of patients were IFN high at baseline. The ANIFR efficacy observed in the entire cohort was similar or more pronounced in IFN high patients. Median suppression of 21 IFN-regulated genes was ~90% for both doses of ANIFR. Serious adverse events were reported in 18.8% of patients on PBO and 16.7% of patients in the pooled ANIFR groups. A higher frequency of influenza (most unconfirmed) (PBO: 1.0%; 300 mg: 6.1%; 1000 mg: 7.6%) and a dosage-dependent increase in Herpes zoster (PBO: 2.0%; 300 mg: 5.1%; 1000 mg: 9.5%) occurred in the ANIFR arms. Conclusion: Anifrolumab significantly reduced disease activity compared with PBO across multiple clinical endpoints. Enhanced effects in IFN high patients support the pathobiology of this treatment strategy. The lack of dose response can be explained by the nearly similar degrees of IFN gene signature inhibition achieved with the two anifrolumab doses. These data strongly support further development of anifrolumab. (Table Presented)

BACKGROUND AND AIMS: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. RESULTS: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs >/=1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to >/=1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). CONCLUSIONS: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.

INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for >/= 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naive B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Background: Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern. Objective: To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE. Design: Prospective cohort. Setting: Multicenter. Patients: 385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE study. Exclusion criteria were urinary protein-creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy. Measurements: APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA). Results: APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 x 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%. Limitation: Patients with high disease activity were excluded. Conclusion: In pregnant patients with inactive or stable mild or moderate SLE, severe flares are infrequent, and absent specific risk factors, outcomes are favorable. Primary Funding Source: National Institutes of Health.

BACKGROUND: The metabolic syndrome (MetS) may contribute to the increased cardiovascular risk in systemic lupus erythematosus (SLE). We examined the association between MetS and disease activity, disease phenotype and corticosteroid exposure over time in patients with SLE. METHODS: Recently diagnosed (<15 months) patients with SLE from 30 centres across 11 countries were enrolled into the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort from 2000 onwards. Baseline and annual assessments recorded clinical, laboratory and therapeutic data. A longitudinal analysis of factors associated with MetS in the first 2 years of follow-up was performed using random effects logistic regression. RESULTS: We studied 1150 patients with a mean (SD) age of 34.9 (13.6) years and disease duration at enrolment of 24.2 (18.0) weeks. In those with complete data, MetS prevalence was 38.2% at enrolment, 34.8% at year 1 and 35.4% at year 2. In a multivariable random effects model that included data from all visits, prior MetS status, baseline renal disease, SLICC Damage Index >1, higher disease activity, increasing age and Hispanic or Black African race/ethnicity were independently associated with MetS over the first 2 years of follow-up in the cohort. CONCLUSIONS: MetS is a persistent phenotype in a significant proportion of patients with SLE. Renal lupus, active inflammatory disease and damage are SLE-related factors that drive MetS development while antimalarial agents appear to be protective from early in the disease course.

OBJECTIVE: To examine the frequency, characteristics, and outcome of mood disorders, as well as clinical and autoantibody associations, in a multiethnic/racial, prospective inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: Patients were assessed annually for mood disorders (4 types, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 18 other neuropsychiatric events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 subscales, mental and physical component summary scores were collected. Time to event, linear and ordinal regressions, and multi-state models were used as appropriate. RESULTS: Among the 1,827 patients with SLE, 88.9% were female, and 48.9% were Caucasian. The mean +/- SD age of the patients was 35.1 +/- 13.3 years, disease duration was 5.6 +/- 4.8 months, and the length of followup was 4.7 +/- 3.5 years. During the course of the study, 863 (47.2%) of the 1,827 patients had 1,627 neuropsychiatric events. Mood disorders occurred in 232 (12.7%) of 1,827 patients, and 98 (38.3%) of 256 mood disorder events were attributed to SLE. The estimated cumulative incidence of any mood disorder after 10 years was 17.7% (95% confidence interval 15.1, 20.2%). A greater risk of mood disorder was associated with concurrent neuropsychiatric events (P