Background/Purpose: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disorder characterized by a waxing and waning clinical course. Predictors of clinical disease flare have been difficult to identify, leading to cumulative damage, therapeutic toxicities and difficulties designing clinical trials. The goal of this study is to identify immunologic associations and pathogenic mechanisms of disease flares in SLE patients no longer taking immunosuppressive medications.

Methods: As part of the Biomarkers of Lupus Disease (BOLD) study, 41 SLE patients with  moderately severe, but not organ-threatening disease activity were enrolled, background immunosuppressants (IS) stopped, intramuscular steroids given until disease suppression and then serially followed until clinical disease flare.  SLE patients met > 4 ACR SLE classification criteria and had SLEDAI > 6 or BILAG >/= 2 B or 1 A scores at baseline. Peripheral blood specimens were collected at baseline, time of disease suppression and serially until they developed a significant enough flare to require new treatment (and minimum >/= 1 new BILAG B or SLEDAI increase of >/= 4 points). 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 a subset of baseline samples from SLE patients.

Results: Forty of 41 SLE patients flared within 24 weeks, with 21 patients flaring within 60 days (early) and 13 flaring greater than 90 days (late) after stopping background IS. Patients who flared early were more likely to be of African-American descent, while Native American patients were more likely to flare late. Compared to late flaring patients, Caucasian SLE patients who flared early overexpressed 69 genes (including MMP9, CD11b (ITGAM), and MYH9) and showed decreased expression of 20 genes, including HLA-DRB5 and IFI6 at baseline. SLE patients who flared early also had higher baseline expression levels of CD11b on neutrophils (p=0.003) and monocytes (p=0.03) and higher CD86 expression on B cells (p=0.03) (all races combined). SLE patients who flared more than 90 days after stopping medications had higher baseline plasma levels of IL-1RA (p=0.03) and TNFRI (p=0.04), as well as higher levels of BLyS (p=0.01), IL-7 (p=0.03) and IFNg (p=0.04) at the flare visit.

Conclusion: SLE patients who will flare earlier after withdrawal of ineffective immunosuppressants and transient steroid treatment have increased levels of activated B cells and increased expression of CD11b at baseline, while SLE patients who flared later have evidence of regulatory pathway engagement through secretion of IL1RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunologic-and-inflammatory-markers-of-impending-disease-flare-in-systemic-lupus-erythematosus-patients-not-taking-immunosuppressive-medications-in-the-biomarkers-of-lupus-disease-bold-study/