ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1103

Systemic Sclerosis Has a Distinct Serum Protein Profile That Correlates with Its Clinical Manifestations

Chiara Bellocchi1,2, Jun Ying3, Ellen Goldmuntz4, Lynette Keyes-Elstein5, John Varga6, Monique Hinchcliff6, Peter McSweeney7, Daniel E. Furst8, Richard Nash7, Leslie Crofford9, Beverly Welch10, Ashley Pinckney5, Maureen D. Mayes11,12, Keith Sullivan13 and Shervin Assassi12, 1University of Texas Health Science Center at Houston, Houston, TX, 2Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 3Department of Internal Medicine - Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 4NIAID, National Institutes of Health, Bethesda, MD, 5Rho Federal Systems, Inc., Chapel Hill, NC, 6Northwestern University, Chicago, IL, 7Colorado Blood Cancer Institute, Denver, CO, 8University of California Los Angeles, Los Angeles, CA, 9Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 10National Institutes of Health, Bethesda, MD, 11Internal Medicine/Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 12Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 13Duke University Medical Center, Durham, NC

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords:

Session Information

Date: Monday, October 22, 2018

Session Title: Systemic Sclerosis and Related Disorders – Basic Science Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Proteomic studies with an extensive panel of measured proteins are still scarce in systemic sclerosis (SSc). The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial showed improved clinical outcomes in participants randomized to myeloablation followed by autologous hematopoietic stem cell transplantation compared to monthly cyclophosphamide (1). In the present study, we performed a proteomic analysis of baseline serum samples collected in the SCOT trial to investigate clinical correlates of serum protein dysregulation at baseline in early diffuse cutaneous SSc (dcSSc).

Methods: A panel of 232 baseline serum proteins in 66 SCOT participants (mean disease duration=2.2 years) compared to 66 age and gender matched controls was analyzed by RBM Human Discovery Multi-Analyte Profiling multiplexed assays. Proteins with levels below the lower limit of detection in more than 50% of SCOT participants, were excluded. Proteins were considered differentially expressed with false discovery rate(FDR) of <5%.

Results: Ninety proteins were differentially expressed in dcSSc versus controls (FDR<0.05). Sixty-five proteins were upregulated, of which 42% (27 molecules) were Type I IFN inducible accordingly to the Interferome database. The ten most up- and down-regulated proteins are presented in Table 1. Serum protein correlates of modified Rodnan Skin Score (mRSS) are shown in Table 2. Carcinoma Antigen 15.3 (CA 15.3) and Epithelial Derived Neutrophil Activating Protein78 (CXCL5) were inversely correlated with forced vital capacity (FVC) (r=-0.33, p<0.006; r=-0.34, p<0.06 respectively) and positively correlated with HRCT fibrosis score (r=0.28, p<0.023; r=0.28, p<0.025) showing an association with lung fibrosis. The Ingenuity Pathway Analysis (IPA) revealed hepatic fibrosis, granulocyte adhesion and diapedesis and agranulocyte adhesion and diapedesis as the top three over-represented pathways, indicating that the serum protein profile of SSc reflects fibrotic as well as immunological dysregulations in SSc.

Conclusion: SSc has a distinct serum protein profile including a prominent upregulation of IFN inducible proteins. The IPA pathway analysis showed top over-represented pathways in SSc serum proteomic analysis parallels those found to be dysregulated in SSc skin global gene expression studies. (2). Finally, we identified several serum proteins that correlate with the extent of skin and lung fibrosis in SSc.

 (1) Sullivan KM, et al. N Engl J Med. 2018 Jan 4;378(1):35-47

(2) Assassi S, et al. Arthritis Rheum. 2015 Nov;67(11):3016-26

 

Table 1: Top up-/ down-regulated serum proteins in SSc vs. control comparison
Protein name Gene name Fold Change P raw P  FDR Direction

Growth Hormone

GH1*

3.69

<0.001

<0.001

Up-regulated

Ferritin

FTH1

3.04

<0.001

<0.001

Up-regulated

C-Reactive Protein

CRP

2.98

<0.001

<0.001

Up-regulated

Chromogranin-A

CHGA

2.77

<0.001

<0.001

Up-regulated

Macrophage inflammatory protein 3 beta

CCL19*

2.48

<0.001

<0.001

Up-regulated

Monocyte Chemotactic Protein 1

CCL2*

2.48

<0.001

<0.001

Up-regulated

Myoglobin

MB

2.38

<0.001

<0.001

Up-regulated

Monokine Induced by Gamma Interferon

CXCL9*

2.30

<0.001

<0.001

Up-regulated

B Lymphocyte Chemoattractant

CXCL13

2.19

<0.001

<0.001

Up-regulated

Prolactin

PRL

2.08

<0.001

<0.001

Up-regulated

Lactoylglutathione lyase

GLO1

0.49

<0.001

<0.001

Down-regulated

Neuron-Specific Enolase

ENO2

0.56

  0.002

  0.007

Down-regulated

Vitamin K-Dependent Protein S

PROS1

0.56

  0.005

  0.013

Down-regulated

Superoxide Dismutase 1

SOD1

0.65

<0.001

<0.001

Down-regulated

Protein S100-A6

S100A6

0.69

  0.002

  0.006

Down-regulated

Macrophage Migration Inhibitory Factor

MIF

0.71

  0.023

  0.046

Down-regulated

Adiponectin

ADIPOQ

0.72

<0.001

<0.001

Down-regulated

Kallikrein-7

KLK7

0.73

<0.001

<0.001

Down-regulated

Insulin like Growth Factor Binding Protein 6

IGFBP6

0.73

<0.001

<0.001

Down-regulated

Tetranectin

CLEC3B

0.75

<0.001

<0.001

Down-regulated

*: type I IFN related protein according to http://interferome.its.monash.edu.au/interferome/

 

Table 2: Serum proteins correlating significantly with mRSS

Protein name

Gene name

Correlation

Adjusted for age, gender

 

r

Pᵘ

b (CI)

Pᵐ

Alpha 1 Antichymotrypsin

SERPINA3

0.42

0.001

9.07 (4.04, 14.12)

0.001

NT proBNP

NPPB

0.38

0.002

3.11 (1.18, 5.04)

0.002

Endostatin

COL18A1

0.37

0.002

12.56 (4.81, 20.31)

0.002

Osteopontin

SPP1

0.34

0.006

7.08 (2.61, 11.56)

0.002

Angiopoietin 2

ANGPT2

0.33

0.005

5.43 (1.51, 9.36)

0.007

Serum Amyloid P Component

APCS

0.32

0.008

9.55 (2.38, 16.72)

0.010

Tenascin C

TNC

0.31

0.011

5.53 (1.36, 9.70)

0.010

Alpha 1 Microglobulin

AMBP

0.31

0.011

8.85 (2.02, 15.69)

0.012

Insulin like Growth Factor Binding Protein 4

IGFBP4

0.30

0.018

5.36 (1.41, 9.31)

0.009

Interleukin 22

IL22

-0.30

0.016

-8.20 (-15.08, -1.32)

0.020

Hepatocyte Growth Factor receptor

MET

-0.30

0.016

-9.63 (-17.08, -2.18)

0.012

Tetranectin

CLEC3B

-0.31

0.011

-11.99 (-20.57, -3.41)

0.007

Kallikrein 5

KLK5

-0.33

0.007

-6.35 (-10.95, -1.77)

0.007

Urokinase type Plasminogen Activator

PLAU

-0.34

0.005

-6.83 (-11.55, -2.12)

0.005

Thymus and activation regulated chemokine

CCL17

-0.35

0.003

-4.10 (-6.80, -1.41)

0.003

Tamm Horsfall Urinary Glycoprotein

UMOD

-0.40

0.001

-7.55 (-11.75, -3.35)

0.001

Macrophage Derived Chemokine

CCL22

-0.43

<0.001

-11.14 (-16.96, -5.31)

<0.001

Epidermal Growth Factor Receptor

EGFR

-0.43

<0.001

-11.61 (-18.02, -5.32)

0.001

r: Pearson correlation coefficient; Pᵘ: p value from univariable model; b: Mean difference in the cytokine per unit of mRSS in the multivariable model; CI: confidence interval; Pᵐ: p value from multivariable model after adjustment for age and gender

 

Disclosure: C. Bellocchi, None; J. Ying, None; E. Goldmuntz, None; L. Keyes-Elstein, None; J. Varga, None; M. Hinchcliff, None; P. McSweeney, None; D. E. Furst, None; R. Nash, None; L. Crofford, None; B. Welch, None; A. Pinckney, None; M. D. Mayes, None; K. Sullivan, None; S. Assassi, None.

To cite this abstract in AMA style:

Bellocchi C, Ying J, Goldmuntz E, Keyes-Elstein L, Varga J, Hinchcliff M, McSweeney P, Furst DE, Nash R, Crofford L, Welch B, Pinckney A, Mayes MD, Sullivan K, Assassi S. Systemic Sclerosis Has a Distinct Serum Protein Profile That Correlates with Its Clinical Manifestations [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/systemic-sclerosis-has-a-distinct-serum-protein-profile-that-correlates-with-its-clinical-manifestations/. Accessed January 23, 2020.

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