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Abstract Number: 2980

Chemokine CCL21 As a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis

Anna-Maria Hoffmann-Vold1, Roger Hesselstrand2, Håvard Fretheim1, Thor Ueland1, Arne K Andreassen1, Oyvind Midtvedt1, Torhild Garen1, Pål Aukrust1, John A Belperio3 and Øyvind Molberg1, 1Oslo University Hospital, Oslo, Norway, 2Lund University, Lund, Sweden, 3University of California, Los Angeles, Los Angeles, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Biomarkers, cytokines and systemic sclerosis, Pulmonary Involvement

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Session Information

Date: Wednesday, November 8, 2017

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Clinical Aspects and Therapeutics III

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose : Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles of chemokines CCL19/21 and their receptor CCR7 in lung inflammation leading to PAH. We aimed to assess the chemokine CCL19/21 axis in SSc-PAH.

Methods: Sera from two independent prospective SSc cohorts including Oslo University Hospital (OUH, n=298) and Lund University Hospital (LU, n=28), idiopathic PAH (n=12) and controls (n=100) were analysed for CCL19/CCL21 by ELISA. Levels were defined as high or low using [mean + 2SD] in controls as cut-off. Risk stratification at time of PAH diagnosis was performed according to 2016 European Society of Cardiology guidelines. PAH related events were defined as; (a) PAH progression (b) end-stage PAH (c) hospitalization for PAH worsening and (d) all-cause mortality.  Cellular sources of CCL21 and CCR7 within SSc-PAH lung tissue were determined by immunohistochemistry.

Results: CCL21 was higher in SSc than controls, and stable across time of PAH diagnosis. Clinical and demographics are shown in Table 1. 129/298 SSc patients underwent RHC at OUH, 41 were diagnosed with PAH and 25 with PH-ILD; at LU 16 patients had PAH. PAH was more frequent in patients with high CCL21 (>0.4 ng/ml) than low CCL21 (33.3% versus 5.3%, p<0.001) and higher than in PH-ILD and idiopathic PH (Figure 1). In multivariate analyses, CCL21 was associated with PAH (HR 5.1 95% CI 2.39-10.76, p<0.001) and predictive for new onset PAH (HR 3.3, 95% CI 1.52-7.10, p=0.003).  CCL21 was associated with occurrence of PAH related events (HR 4.7, 95%CI 2.12-10.46, p<0.001). Risk stratification at PAH diagnosis alone did not predict PAH related events, but when combined with CCL21 (HR 1.3, 95% C 1.03-1.60, p=0.027). Survival at 5- and 10-years differed between high and low CLL21 subsets (87% and 71% versus 96% and 91%, p<0.001). Main cellular sources of CCL21 in SSc-PAH lungs were vascular endothelial cells and circulating mononuclear cells (Figure 2), while CCR7 marked infiltrating vascular wall mononuclear cells.

Conclusion: CCL21 appears as a promising marker for SSc-PAH risk prediction and PAH progression. CCL21 may be part of a deregulated immune pathway linked to development of lung vascular damage in SSc.

Table 1:

 

Total

 

SSc-PH

 

iPAH

 

 

 

PAH

PAH

PH-ILD

 

 

OUH

(n=298)

OUH

(n=41)

LU†

(n=16)

OUH

(n=25)

OUH

(n=12)

Age at onset, yrs

56 (13.9)

66.8 (8.2)

68.6(10.3)

59.5(10.2)

40.3(14.5)

Time from onset to PH, yrs

n.a.

12.1(10.8)

15.2 (6.5)

8.7 (5.6)

0 (0)

Time from sera sampling to PH, yrs

n.a.

-2.1 (3.8)

-2.6 (0.7)

-1.4 (2.7)

0.07 (1.2)

Males, no (%)

55(18.5)

9 (22)

2 (12.5)

9 (36)

2 (16.7)

Deceased, no (%)

99 (31.6)

21 (51.2)

11 (68.8)

15 (60)

4 (33.3)

Diffuse cutaneous SSc, no (%)

78 (26.2)

4 (9.8)

0 (0)

6 (24)

n.a.

Anti-centromere Ab, no (%)

127(46.9)

25 (69.4)

8 (50)

5 (20)

n.a.

mPAP at diagnosis, mmHg

n.a.

39.1(11.9)

38.5(10.1)

36.3(11.6)

55.1(17.1)

CCL21 at baseline, pg/ml

 

0.51 (0.2)

0.60 (0.3)

0.33 (0.1)

0.26 (0.1)

 

Figure 1:

Figure 2:

 


Disclosure: A. M. Hoffmann-Vold, None; R. Hesselstrand, None; H. Fretheim, None; T. Ueland, None; A. K. Andreassen, None; O. Midtvedt, None; T. Garen, None; P. Aukrust, None; J. A. Belperio, None; Ø. Molberg, None.

To cite this abstract in AMA style:

Hoffmann-Vold AM, Hesselstrand R, Fretheim H, Ueland T, Andreassen AK, Midtvedt O, Garen T, Aukrust P, Belperio JA, Molberg Ø. Chemokine CCL21 As a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/chemokine-ccl21-as-a-potential-serum-biomarker-for-pulmonary-arterial-hypertension-in-systemic-sclerosis/. Accessed January 18, 2021.
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