Stratification of Systemic Lupus Erythematosus Patients Into Three Groups of Disease Activity Progression According to Longitudinal Gene Expression

Toro-Domínguez, Daniel; Martorell-Marugán, Jordi; Goldman, Daniel; Petri, Michelle; Carmona-Sáez, Pedro; Alarcón‐Riquelme, Marta E.

doi:10.1002/art.40653

Cited by 88 publications

(86 citation statements)

References 35 publications

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“…All of these approaches have taught us something, but it has long been suspected that these distinctions are somewhat incomplete, and that the next step must be to examine a more comprehensive set of immune variables. Our work and others who have utilized gene co-expression module signatures with or without the integration of soluble mediators [13,30,32,33] confirms that many features that can somewhat define patient subsets, such as autoantibodies or nephritis, are found in immunologically distinct patients who may benefit more or less from given combinations of immune modulating treatments.…”

Section: Discussionsupporting

confidence: 75%

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

Guthridge

Tran

et al. 2020

EClinicalMedicine

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A B S T R A C TBackground: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering. Methods: Adult SLE patients (n = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray geneexpression data. Plasma soluble mediators (n = 23) and autoantibodies (n = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. Findings: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-a, IP10, and IL-1a levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters. Interpretation: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches.

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Section: Discussionsupporting

confidence: 75%

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

Guthridge

Tran

et al. 2020

EClinicalMedicine

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“…Two of these studies proposed stratification schemes based on the correlations of molecular parameters with SLEDAI score. In each scheme, the assignment of an individual patient to a cohort required longitudinal data (29,36). Importantly, the correlations of specific groups of genes or signatures with disease activity suggest that different molecular pathways can contribute to active disease in patient groups, similar to what we propose here with respect to plasmablast derivation.…”

Section: Discussionmentioning

confidence: 62%

“…Several studies have attempted to stratify SLE patients, most using gene expression profiles of peripheral leukocytes or subsets thereof, such as T cells or neutrophils (29,(35)(36)(37). Most of these studies have focused on correlations with disease activity or clinical symptoms, such as nephritis.…”

Section: Discussionmentioning

confidence: 99%

“…Most of these studies have focused on correlations with disease activity or clinical symptoms, such as nephritis. These studies revealed correlations of plasmablast signatures and IFN signatures with disease activity in pediatric patients (29) and correlations of neutrophil signatures with lupus nephritis (29,36). Two of these studies proposed stratification schemes based on the correlations of molecular parameters with SLEDAI score.…”

Section: Discussionmentioning

confidence: 99%

“…We believe the most important question is whether any proposed classification can identify those patients most likely to respond to a given therapeutic agent. Although providing novel insights into the heterogeneity of SLE, the stratifications proposed in the studies mentioned above often require multiple longitudinal measurements to determine patient clusters (29,36), thereby limiting their applicability for stratifying patients going into clinical trials. While we currently cannot answer the question whether our classification will predict a response to particular therapy, this question can be addressed by using our methodology to analyze patients entering clinical trials with the methods we present.…”

Section: Discussionmentioning

confidence: 99%

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Patterns of ANA+ B cells for SLE patient stratification

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Low‐Density Neutrophils in Systemic Lupus Erythematosus

Tay

Celhar

Fairhurst

2020

Arthritis & Rheumatology

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Patients with systemic lupus erythematosus ( SLE ) display increased numbers of immature neutrophils in the blood, but the exact role of these immature neutrophils is unclear. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low‐density neutrophils ( LDN s). Far beyond antimicrobial functions, LDN s are emerging as decision‐shapers during innate and adaptive immune responses. Traditionally, neutrophils have been viewed as a homogeneous population. However, the various LDN populations identified in SLE to date are heterogeneously composed of mixed populations of activated mature neutrophils and immature neutrophils at various stages of differentiation. Controversy also surrounds the role of LDN s in SLE in terms of whether they are proinflammatory or polymorphonuclear myeloid‐derived suppressor cells. It is clear that LDN s in SLE can secrete increased levels of type I interferon ( IFN ) and that they contribute to the cycle of inflammation and tissue damage. They readily form neutrophil extracellular traps, exposing modified autoantigens and oxidized mitochondrial DNA , which contribute to autoantibody production and type I IFN signaling, respectively. Importantly, the ability of LDN s in SLE to perform canonical neutrophil functions is polarized, based on mature CD 10+ and immature CD 10− neutrophils. Although this field is still relatively new, multiomic approaches have advanced our understanding of the diverse origins, phenotype, and function of LDN s in SLE . This review updates the literature on the origin and nature of LDN s, their distinctive features, and their biologic roles in the immunopathogenesis and end‐organ damage in SLE .

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Stratification of Systemic Lupus Erythematosus Patients Into Three Groups of Disease Activity Progression According to Longitudinal Gene Expression

Cited by 88 publications

References 35 publications

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

Patterns of ANA+ B cells for SLE patient stratification

Low‐Density Neutrophils in Systemic Lupus Erythematosus

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