ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1842

Subsetting Systemic Lupus Erythematosus By Interferon Gene Signatures and Serologies (anti-dsDNA and Low Complement) Uncovers Significant Clinical Diversity

Michelle Petri1, Steven Watts2, Richard Higgs2, MaryAnn Morgan-Cox2 and Matthew D Linnik3, 1Medicine (Rheumatology), Division of Rheumatology, Johns Hopkins University School of Medicine, MD, USA, Baltimore, MD, 2Eli Lilly and Company, Indianapolis, IN, 3Immunology, Lilly Biotechnology Center, San Diego, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: , ,

Session Information

Date: Monday, November 6, 2017

Title: Systemic Lupus Erythematosus – Clinical Aspects and Treatment II: Clinical Trial Design and Outcome Measures

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:   Personalized therapy in systemic lupus erythematosus (SLE) will require identifying SLE subsets that will benefit from different targeted therapies.  Belimumab, for example, has the highest response rates in those with low complement and high anti-DNA, whereas anifrolumab (anti-interferon receptor alpha) has the highest response rates in those with the interferon alpha gene signature. 

Methods:   Objective molecular and biochemical baseline parameters were obtained to characterize SLE patients in two large multinational trials (n=2262 patients).  Patients were categorized with three dichotomous baseline parameters:  IFN gene signature, anti-dsDNA, and C3/C4. 

Results:   Table 1 shows the different subgroups of those with or without interferon gene signature grouped by serologies.  Table 2 contains the p-values. 

Table 1. 

Subgroup Criteria

IFN Positive Groups

IFN Negative Groups

SLE Group 1

SLE Group 2

SLE Group 3

SLE Group 4

SLE Group 5

SLE Group 6

SLE Group 7

SLE Group 8

IFN (-)*

IFN

(+)

(+)

(+)

(+)

(-)

(-)

(-)

(-)

(-)

Anti-dsDNA

(+)

(-)

(+)

(-)

(+)

(+)

(-)

(-)

either

Low C3 or C4

(+)

(-)

(-)

(+)

(-)

(+)

(+)

(-)

either

n=536

n=351

n=316

n=115

n=104

n=46

n=32

n=247

n=429

Baseline SLEDAI

SLEDAI (mean)

12.4

8.9

10.1

10.7

10.1

11.1

9.8

8.3

9.2

SLEDAI ≥ 10 (%)

80.2

37.3

54.4

67.8

63.5

80.4

65.6

27.9

45.0

Baseline Concomitant Medications

Corticosteroids (%)

89.4

67.2

75.3

75.7

68.3

82.6

53.2

49.0

57.6

Antimalarials (%)

64.6

65.0

68.4

72.2

66.4

67.4

75.0

72.1

70.4

Immunosuppressants (%)

47.2

40.7

40.2

52.2

42.3

34.8

34.4

31.2

34.5

Azathioprine (%)

22.2

16.0

20.9

25.2

19.2

17.4

21.9

10.5

14.2

MTX (%)

10.1

15.1

11.7

20.0

8.7

6.5

6.3

15.4

12.1

MMF (%)

12.7

7.4

7.0

10.4

11.5

8.7

3.1

3.6

6.1

Baseline Organ Involvement (SLEDAI)

CNS (%)

0.8

2.6

2.9

1.7

1.0

0.0

0.0

3.2

2.1

Vascular (%)

10.3

7.4

6.0

10.4

5.8

4.4

3.1

2.4

3.5

Musculoskeletal (%)

79.7

94.3

87.0

87.0

90.4

87.0

90.6

95.2

92.8

Renal (%)

15.1

3.7

6.0

6.1

10.6

6.5

3.1

4.5

6.1

Mucocutaneous (%)

87.9

96.9

89.2

94.8

84.6

82.6

90.6

96.0

91.4

CV/Respiratory (%)

10.3

6.3

5.7

7.0

6.7

8.7

6.3

9.3

8.4

Immunologic (%)

99.8

12.0

99.4

99.1

100.0

100.0

96.9

5.3

45.2

Constitutional (%)

1.7

2.0

2.2

3.5

1.0

2.2

0.0

0.8

0.9

Hematologic (%)

13.4

6.0

9.8

13.0

2.9

8.7

3.1

1.6

2.8

* Combination of Groups 5-8. 

Table 2. *

P-values IFN (-) Combined Groups versus

P-values Group 2 versus

Group 1

Group 2

Group 3

Group 4

Group 1

Group 3

Group 4

IFN

(+)

(+)

(+)

(+)

(+)

(+)

(+)

Anti-dsDNA

(+)

(-)

(+)

(-)

(+)

(+)

(-)

Low C3 or C4

(+)

(-)

(-)

(+)

(+)

(-)

(+)

Baseline SLEDAI

SLEDAI (mean)

<0.0001

0.3378

0.0006

<0.0001

<0.0001

<0.0001

<0.0001

SLEDAI ≥ 10 (%)

<0.0001

0.0370

0.0108

<0.0001

<0.0001

<0.0001

<0.0001

Baseline Concomitant Medications

Corticosteroids (%)

<0.0001

0.0057

<0.0001

0.0004

<0.0001

0.0216

0.0894

Antimalarials (%)

0.0548

0.1054

0.5496

0.7097

0.9018

0.3531

0.1540

Immunosuppressants (%)

<0.0001

0.0729

0.1116

0.0005

0.0584

0.8849

0.0319

Azathioprine (%)

0.0016

0.4995

0.0168

0.0048

0.0222

0.1000

0.0256

MTX (%)

0.3123

0.2253

0.8638

0.0295

0.0246

0.2006

0.2170

MMF (%)

0.0006

0.4531

0.6204

0.1022

0.0125

0.8241

0.3032

Baseline Organ Involvement (SLEDAI)

CNS (%)

0.0703

0.6662

0.5099

0.8082

0.0276

0.8212

0.6130

Vascular (%)

<0.0001

0.0149

0.1039

0.0023

0.1491

0.4733

0.3032

Musculoskeletal (%)

<0.0001

0.3904

0.0087

0.0465

<0.0001

0.0011

0.0095

Renal (%)

<0.0001

0.1330

0.9783

0.9916

<0.0001

0.1636

0.2738

Mucocutaneous (%)

0.0787

0.0015

0.3267

0.2291

<0.0001

<0.0001

0.3010

CV/Respiratory (%)

0.3234

0.2607

0.1608

0.6162

0.0389

0.7562

0.7940

Immunologic (%)

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

Constitutional (%)

0.3174

0.2108

0.1514

0.044

0.7302

0.8425

0.3630

Hematologic (%)

<0.0001

0.0279

<0.0001

<0.0001

0.0004

0.0657

0.0138

*p-values are from pairwise tests

Comparing negative interferon gene signature with the four interferon gene signature positive groups showed that interferon gene signature negative patients were more likely to have musculoskeletal activity than interferon gene signature positive Groups 1, 3, and 4; and more likely to have mucocutaneous activity than Group 2.  Comparing Group 2 (interferon gene signature alone with no serologies) versus the other three interferon gene signature positive groups showed that the other groups had more activity and required more treatment.  However, Group 2 was more likely than the other interferon gene signature groups to have musculoskeletal and mucocutaneous activity. 

Conclusion:   Subsetting SLE by BOTH interferon alpha gene signature AND serologies is much more informative than just the interferon alpha gene signature alone.  There is tremendous, highly statistically significant clinical diversity within the interferon positive subgroups.  This suggests that results for clinical trials of interferon targeted therapy should include such subset analyses. 

Disclosure: M. Petri, Anthera Inc, 5,GlaxoSmithKline, 5,EMD Serono, 5,Eli Lilly and Company, 5,Bristol Meyer Squibb, 5,Amgen, 5,United Rheumatology, 5,Global Academy, 5,Exagen, 2; S. Watts, Eli Lilly and Company, 1,Eli Lilly and Company, 3; R. Higgs, Eli Lilly and Company, 1,Eli Lilly and Company, 3; M. Morgan-Cox, Eli Lilly and Company, 1,Eli Lilly and Company, 3; M. D. Linnik, Eli Lilly and Company, 1,Eli Lilly and Company, 3.

To cite this abstract in AMA style:

Petri M, Watts S, Higgs R, Morgan-Cox M, Linnik MD. Subsetting Systemic Lupus Erythematosus By Interferon Gene Signatures and Serologies (anti-dsDNA and Low Complement) Uncovers Significant Clinical Diversity [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/subsetting-systemic-lupus-erythematosus-by-interferon-gene-signatures-and-serologies-anti-dsdna-and-low-complement-uncovers-significant-clinical-diversity/. Accessed .

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