Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus

Abstract

Objective. Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. Methods. Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. Results. Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). Conclusion. These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE. ClinicalTrials.gov identifier: NCT01438489.

Interferon lambda in inflammation and autoimmune rheumatic diseases

“…Anifrolumab also reduced glucocorticoid use and improved skin disease in TULIP-2. Further analysis from a phase IIb trial showed that anifrolumab could reduce markers of cardiometabolic dysfunction in patients with SLE, suggesting that it might have additional benefit in SLE vasculopathy 123 . Anifrolumab is also being evaluated in a phase II trial for patients with active proliferative lupus nephritis 124 .…”

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

“…Notably, IFN-κ production by keratinocytes may be an early step in driving lupus skin disease, where IFN- κ is proposed to activate dendritic cells, amplify IFN-α responses, and contribute to skin photosensitivity [ 26 , 87 ]. Type I interferon has also been implicated in cardiovascular disease in patients with SLE, with multiple studies identifying an association between type I interferon dysregulation and subclinical and clinical cardiovascular disease markers, independent of known cardiovascular risk factors [ 88 , 89 , 90 ].…”

“…As well as showing improvements in clinical outcomes, anifrolumab treatment was associated with reduced levels of inflammatory and cardiometabolic disease markers in a phase two trial [ 90 , 131 ]. Patients with SLE were at a three- to four-fold greater risk of experiencing cardiovascular events than healthy controls (adjusting for known risk factors such as age, sex, and smoking history), as a result of immune-mediated vascular damage and premature atherosclerosis [ 134 ].…”

“…Patients with SLE were at a three- to four-fold greater risk of experiencing cardiovascular events than healthy controls (adjusting for known risk factors such as age, sex, and smoking history), as a result of immune-mediated vascular damage and premature atherosclerosis [ 134 ]. Anifrolumab treatment significantly modulated levels of multiple subclinical markers of cardiometabolic disease that contribute to SLE vasculopathy, suggesting that inhibiting type I IFN signaling could reduce atherosclerosis and cardiovascular markers in patients with SLE [ 90 ].…”

Identification of a Novel Serum Proteomic Signature for Primary Sjögren’s Syndrome

“…Proteomic techniques consider the multifactorial processes involved, and their more global approach may provide a more complete picture of the disease ( 11 ). Multiplex immunoassays are promising and have allowed for the identification of interesting biomarkers in AIDs ( 12 – 15 ). Such an approach may soon be available in clinical practice despite limitations such as interference by highly concentrated proteins and cross-reactivity ( 16 ).…”