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Abstract Number: 1877

A Neutrophil Signature Comprised Of Low Density Granulocyte (LDG)-Enriched Genes Is Associated With Organ-Specific Disease Activity In Systemic Lupus Erythematosus

Michelle Petri1, Hong Fang1, Jadwiga Bienkowska2, Andrea Dearth3, Norm Allaire4 and Ann Ranger3, 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Translational Medicine, Biogen Idec Inc., Cambridge, MA, 3Biogen Idec Inc, Cambridge, MA, 4Biogen Idec Inc., Cambridge, MA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Disease Activity, neutrophils and systemic lupus erythematosus (SLE)

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Session Information

Session Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

M. Petri,

Biogen Idec Inc,

2,

Biogen Idec Inc,

5;

H. Fang,
None;

J. Bienkowska,

Biogen Idec Inc,

1,

Biogen Idec Inc,

3;

A. Dearth,

Biogen Idec Inc,

1,

Biogen Idec Inc,

3;

N. Allaire,

Biogen Idec Inc,

1,

Biogen Idec Inc,

3;

A. Ranger,

Biogen Idec Inc,

1,

Biogen Idec Inc,

3.

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