Immunologic findings precede rapid lupus flare after transient steroid therapy

Abstract

Systemic lupus erythematosus (SLE) flares elicit progressive organ damage, leading to disability and early mortality. This study evaluated clinical and immunologic factors associated with impending flare in the Biomarkers of Lupus Disease study. Autoantibodies and 32 soluble mediators were measured by multiplex assays, immune pathway activation by gene expression module scores, and immune cell subset frequencies and activation states by flow cytometry. After providing baseline samples, participants received transient steroids to suppress disease and were followed until flare. Flare occurred early (within 60 days of baseline) in 21 participants and late (90–165 days) in 13. At baseline, compared to the late flare group, the early flare group had differential gene expression in monocyte, T cell, interferon, and inflammation modules, as well as significantly higher frequencies of activated (aCD11b + ) neutrophils and monocytes, and activated (CD86 hi ) naïve B cells. Random forest models showed three subgroups of early flare patients, distinguished by greater baseline frequencies of aCD11b + monocytes, or CD86 hi naïve B cells, or both. Increases in these cell populations were the most accurate biomarkers for early flare in this study. These results suggest that SLE flares may arise from an overlapping spectrum of lymphoid and myeloid mechanisms in different patients.

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

“…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.…”

“…The mean inter-assay coefficient of variance (CV) of these assays (10¢5%) was within that previously shown for bead-based assays [29]. Limit of blank, limit of detection, and limit of quantification were determined and used for quality control as previously described [30]. Analytes with >60% of samples below the limit of detection were excluded from subsequent analyses.…”

Epstein-Barr Functional Mimicry: Pathogenicity of Oncogenic Latent Membrane Protein-1 in Systemic Lupus Erythematosus and Autoimmunity

“…More complete understanding of immune dysregulation in SLE will facilitate proactive interventions with the potential to delay and minimize transition to disease classification, clinical disease flare, and permanent organ damage ( 5 , 92 ). Despite the ability of a multitude of studies to elucidate genetic risk and highlight immune parameters that may be influenced by genetic variance ( 12 , 13 ), genetic variation alone incompletely explains lupus pathogenesis.…”

“…LMP1 drives additional forms of immune dysregulation that contribute to SLE disease pathogenesis ( 3 ), clinical disease activity and flare ( 5 – 7 ), including type I IFN and Th1-, Th2-, and Th17-type immunity. Type I IFN is produced in response to LMP1-mediated IRF7 stimulation ( 84 ), in conjunction with other TLRs, including TLR3 and TLR9 ( 117 – 120 ) ( Figure 11 -3).…”

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

“…However, an IFN signature is found in only 50-80% of SLE patients (Baechler et al, 2003;Bennett et al, 2003;Crow and Wohlgemuth, 2003) and the IFN-induced gene signature assessed in longitudinal studies may not correlate with disease activity (Landolt-Marticorena et al, 2009;Petri et al, 2009). Indeed, in addition to IFN modules, other gene modules have been variably reported to associate with SLE clinical features (Banchereau et al, 2016;Rai et al, 2016;Lu et al, 2019;Barturen et al, 2020;Guthridge et al, 2020). These data indicate that IFN does not account for all pathological and clinical aspects of SLE, which may be further explained by heterogeneity in the IFN-I pathway activation and genetic makeup (Kariuki et al, 2015).…”