Brief Report: Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti–Interferon‐γ Antibody, in Patients With Discoid Lupus Erythematosus

Werth, Victoria P.; Fiorentino, David; Sullivan, Barbara A.; Boedigheimer, Michael; Chiu, Kit; Wang, Christine; Arnold, Gregory E.; Damore, Michael A.; Bigler, Jeannette; Welcher, Andrew A.; Russell, Chris B.; Martin, David; Chung, James B.

doi:10.1002/art.40052

Cited by 65 publications

(32 citation statements)

References 16 publications

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“…It has been well documented that certain stimuli possessing immunostimulatory activities can accelerate SLE mortality in mice by inducing the generation of IFN‐α (Fagone, Mangano, et al, ; Fagone, Muthumani, et al, ). IFN‐blocking strategies have also been studied as promising effective treatments for SLE (Welcher et al, ; Werth et al, ). The study by Ouyang et al () has demonstrated potential use of the human antibody for modulating the activity of IFN‐α in murine SLE.…”

Section: Discussionmentioning

confidence: 99%

Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus

Yan

Wang

Gao

et al. 2018

Journal Cellular Physiology

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We performed a systematic review of genome-wide gene expression datasets to identify key genes and functional modules involved in the pathogenesis of systemic lupus erythematosus (SLE) at a systems level. Genome-wide gene expression datasets involving SLE patients were searched in Gene Expression Omnibus and ArrayExpress databases. Robust rank aggregation (RRA) analysis was used to integrate those public datasets and identify key genes associated with SLE. The weighted gene coexpression network analysis (WGCNA) was adapted to identify functional modules involved in SLE pathogenesis, and the gene ontology enrichment analysis was utilized to explore their functions. The aberrant expressions of several randomly selected key genes were further validated in SLE patients through quantitative real-time polymerase chain reaction. Fifteen genome-wide gene expression datasets were finally included, which involved a total of 1,778 SLE patients and 408 healthy controls. A large number of significantly upregulated or downregulated genes were identified through RRA analysis, and some of those genes were novel SLE gene signatures and their molecular roles in etiology of SLE remained vague. WGCNA further successfully identified six main functional modules involved in the pathogenesis of SLE. The most important functional module involved in SLE included 182 genes and mainly enriched in biological processes, including defense response to virus, interferon signaling pathway, and cytokine-mediated signaling pathway. This study identifies a number of key genes and functional coexpression modules involved in SLE, which provides deepening insights into the molecular mechanism of SLE at a systems level and also provides some promising therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus

Yan

Wang

Gao

et al. 2018

Journal Cellular Physiology

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“…Furthermore, AMG811, a monoclonal antibody depleting IFN-g, was tested in a phase I trial in LE. IFN-gassociated biomarkers decreased, even if there was no clinical effect on LE skin lesions after administration of one single dose (Werth et al, 2017). Phase II studies with different dosage regimes ought to clarify if there is a beneficial effect.…”

Section: Discussionmentioning

confidence: 99%

Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis

Lauffer

Jargosch

Krause

et al. 2018

Journal of Investigative Dermatology

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Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-γ and tumor necrosis factor alpha (TNF-α) positive cells. The transcriptome of keratinocytes stimulated with IFN-γ and TNF-α correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-γ, TNF-α, or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant-an effect that was dependent on the presence of either IFN-γ or TNF-α in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-γ or TNF-α. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis.

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“…For example, neutralization of IFN-γ was shown to ameliorate disease in a mouse model of SLE and IFN-γ antagonism was shown to downregulate IFN signature genes in SLE patients [97, 98]. However, downregulation of IFN signature genes mediated by therapeutic IFN-γ antagonism failed to coincide with clinical improvement in patients with discoid lupus [99]. Much work remains to be done in optimizing this therapeutic approach.…”

Section: Future Directions and Therapeutic Perspectivesmentioning

confidence: 99%

Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency

Maglione

Cols

Cunningham‐Rundles

2017

Curr Allergy Asthma Rep

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Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.

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Brief Report: Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti–Interferon‐γ Antibody, in Patients With Discoid Lupus Erythematosus

Cited by 65 publications

References 16 publications

Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus

Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus

Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis

Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency

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