Background/Purpose:

The neutrophil gene signature (NGS) has recently gained interest due to new understanding of the role of neutrophils and NETosis in SLE pathogenesis. We explored the association of a neutrophil gene signature comprised of genes significantly upregulated in low-density granulocytes (LDGs) with both global and organ specific disease activity in SLE patients.

Methods:

Of 292 SLE patients, 91.1% were female; 58.9% Caucasian, 33.9% African-American, and 7.2% other ethnicities. Mean age (standard deviation) at baseline was 46.0 (±11.9) years. Gene expression levels were assessed in peripheral blood RNA samples using microarray (Affymetrix). The LDG-associated gene signature was comprised of 8 genes significantly upregulated in LDGs relative to normal-density neutrophils. The LDG-associated signature “score” was calculated based on the geometric mean of the expression levels (chip signal intensity) of the 8 genes in the signature. The patients were divided into three roughly equal sized groups based on neutrophil signature “scores”, and the groups compared with respect to same-day disease activity.  Adjusted p-values were calculated using generalized linear models controlling for ethnicity (SAS 9.2).

Results:

The NGS was high (>6) in 31.9% (N=93), medium (5-6) in 31.5% (N=92), and low (<5) in 36.6% (N=107) of patients. The LDG-associated NGS was associated with same day global activity measured both by the physician global assessment >1 (on a 0 to 3 VAS) and by SLEDAI ≥2. It was associated with renal activity by VAS, arthritis by SLEDAI, anti-dsDNA, low complement, and alopecia. It was negatively associated with the hematologic VAS.

Table 1:  Association between same-day disease activity and neutrophil signature in SLE

 

Variable	Low Neutrophil (<5) (% patients N=107)	Med Neutrophil (5-6) (% patients N=92)	High Neutrophil (>6) (% patients N=93)	Adjusted P-value for Ethnicity	Adjusted P-value for Ethnicity, Low/Med vs High
Physician’s global assessment >1	11.2	16.3	30.1	0.003	0.0011
Rash >0	27.1	33.7	33.3	0.19	0.093
Joints >0	25.2	32.6	37.6	0.15	0.12
Serositis >0	0.9	1.1	2.2	0.65	0.36
Neurologic >0	0	2.2	3.2	0.078	0.14
Renal >0	14.0	12.0	28.0	0.0085	0.0024
Hematologic >0	24.3	13.0	9.7	0.0096	0.020
SELENA SLEDAI ≥2	47.7	60.9	65.6	0.012	0.015
Hematuria	0.9	0	3.2	0.091	0.062
Proteinuria	5.6	4.4	10.8	0.18	0.072
Arthritis	0	1.1	6.5	0.0073	0.0023
Low complement	12.2	13.0	24.7	0.066	0.020
Anti-dsDNA	10.3	26.1	31.2	0.0005	0.011
Rash	2.8	7.6	7.5	0.21	0.47
Alopecia	18.7	23.9	28.0	0.011	0.0030
Mucous membrane	3.7	3.3	3.2	0.95	0.77
Pleurisy	1.0	1.1	2.2	0.65	0.36
Platelet<100	2.8	2.2	1.1	0.62	0.35
WBC<3	2.8	1.1	3.2	0.50	0.45

Conclusion:

The LDG-associated gene signature was strongly associated with both global and organ-specific activity, being positively associated with arthritis and renal disease. Subsetting patients by neutrophil gene signature may be helpful in clinical trials of new biologics in SLE. In those patients with renal and musculoskeletal activity, LDGs may be a promising therapeutic target.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-neutrophil-signature-comprised-of-low-density-granulocyte-ldg-enriched-genes-is-associated-with-organ-specific-disease-activity-in-systemic-lupus-erythematosus/