Background/Purpose: The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. Predicting which patients are likely to develop high disease activity (flare more) after remission have been generally limited to assessing autoantibodies, complement products and select serum cytokine levels, such as BLyS. The goal of this study is to identify immunologic markers and molecular mechanisms associated with flare intensity in SLE patients no longer taking immunosuppressive medications. 

Methods: As part of the Biomarkers of Lupus Disease (BOLD) study, 41 patients with ACR Classification Criteria for SLE, with  moderately severe, but not organ-threatening disease activity, (SLEDAI > 6 and/or BILAG > 2 B or 1 A) were enrolled, background immunosuppressants (IS) stopped, intramuscular steroids given until disease suppression and then serially followed until clinical disease flare. In addition to autoantibody levels and extensive immunophenotyping, 52 soluble inflammatory mediators, including cytokines, chemokines, and soluble receptors, using either xMAP multiplex technology or sandwich ELISA (BLyS and APRIL), were measured. Gene expression profiling, with globin depletion, was performed on the subset of patients with available whole blood RNA samples.

Results: Hierarchical clustering of longitudinal SLEDAI profiles identified two distinct subgroups of SLE patients. After improvement, 17 patients demonstrated higher disease activity (“flare more” group), in contrast with 15 patients showing more moderate flare activity (“flare less” group) (p=0.007). At the baseline visit, SLE patients from the “flare more” group overexpressed 133 genes (including HLA-DQB1, CXCL5, IL15RA, CD74, and ELK1) and showed decreased expression of 104 genes, including CLEC12A, MAX, FCAR, IL4R, IL25. The patterns of differentially expressed genes were suggestive of active IFNg signaling (z-score=2.1) and inhibited CD28 signaling (z-score=-2.4). The “TNF alpha/NFkB signaling” was the most overrepresented pathway (p=0.003).

SLE patients who flared more had higher baseline plasma levels of Eotaxin (CCL11, p=0.03), and MCP-1 (CCL13, p=0.03) and TRAIL (TNFSF10, p=0.04) increased at the flare visit. They also exhibited decreased monocyte (p=0.03) and neutrophil (p=0.04) counts at the baseline visit, and decreased CD80 (p=0.04) at the flare visit. On the contrary, CD4+ T cells counts were increased (p=0.05) at baseline visit in the “flare more” group.

Conclusion: SLE patients who will flare more after withdrawal of ineffective immunosuppressants and transient amelioration of disease with steroid treatment have gene expression, cytokine protein levels and immunophenotyping biomarker signatures indicative of 1.) abnormal antigen presentation signaling manifested by decreased co-stimulatory signals, (CD80, CD28), 2.) chemoattraction of eosinophils and monocytes, and 3.) potential activation of NFkB signaling through TRAIL binding, antagonizing cell death and promoting inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunologic-markers-and-molecular-mechanisms-associated-with-increased-systemic-lupus-erythematosus-activity-in-patients-not-taking-immunosuppressive-medications/