Background/Purpose: The objective of this study was to evaluate for an association between various biomarkers and the presence or absence of pulmonary hypertension (PH) in scleroderma

Methods: Proteomic analysis was used to retrospectively compare growth factor and cytokine levels in 48 patients with scleroderma and PH and 48 patients with scleroderma without clinical or ECHO evidence of PH.  PH was defined as either an mPAP ≥ 25mmHg by right heart catheterization (n = 44) or an RVSP of > 45 mmHg by Echo with strong clinical evidence supporting a diagnosis (n= 4). An additional proteomic analysis was performed on a subset of 24 patients from each group using samples that had been drawn at least 6 months prior to the first sample to determine if changes in candidate biomarker levels were associated with PH. A multiplex proteomic assay was subsequently performed to look at growth factors (bFGF, PIGF, VEGF, HGF, sFLT-1) and cytokine levels (IL 1B, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12 p70, IL-13, TNF-alpha, and INF-gamma) (MesoScale Discovery, Gaithersburg, MD). Univariate and multivariable logistic regression were used to examine the association of growth factor and cytokine levels with the presence of pulmonary hypertension.

Results:

The mean age in the PH group was 66 yrs (range 34-89) compared to 56 (range 27-83) in the non-PH group.  Seventy-three percent (n=35) in the PH group had limited scleroderma compared to 65% (n=31) in the control group. Average disease duration was 17.3 years in the PH group and 12.2 years in the non-PH group.  Differences in gender and scleroderma subtype were not significant between the two groups. We found levels of IL-12 p70 (9.0 vs. 4.0; p=0.04), PlGF (26.7 vs. 21.3, p = 0.01), and sFLT-1(122.1 vs. 99.1, p=0.02) were significantly higher in the 48 patients with PH compared with the 48 without PH at the latest blood sampling time point. When comparing biomarker levels at the earlier time point (17/24 with sample prior to PH diagnosis in the PH group) in the 24 patients with and 24 patients without pulmonary hypertension, sFLT-1 (122.2 vs. 100.5; p= 0.0062; CI -36.87, -6.52), HGF (451.6 vs. 202.1; p =0.003; CI  -403.79,  -95.28), and IL-10 (12.6 vs. 4.4; p= 0.03; CI -15.67, -.85), were significantly higher in the PH group. In a multivariable model adjusted for age, race, disease duration, and ILD, PlGF remained higher among those with PH (OR 1.06, p=0.16) although this was no longer statistically significant. In examining the stability of markers over time, all biomarkers were stable between the two samples except for VEGF (260.8 vs. 546.1; p=0.001) and bFGF (19.8 vs. 11.1; p= 0.01) which showed wide variability in levels between patients and at the 2 time points.  IL-12p70 (-0.24, p = 0.05, CI -0.48, -0.00) and IL-5 (-0.51, p= 0.03, CI -0.952, -0.059) were negatively associated with severity of pulmonary hypertension as measured by mean pulmonary artery pressures (mPAP) among those with PH.

Conclusion: We found that PlGF (and possibly sFLT-1 and IL-12) may be associated with PH in scleroderma. This study confirms prior associations of PlGF with scleroderma vascular disease and suggests that this factor should be further explored as possible biomarkers of development of PH.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-of-pulmonary-hypertension-in-patients-with-scleroderma-a-case-control-study/