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Plasma GDF-15 and PSP-D Predict the Development of Pulmonary Arterial Hypertension in Systemic Sclerosis

Engel Sällberg, Adam LU orcid ; Ahmed, Salaheldin LU orcid ; Ahmed, Abdulla LU orcid ; Kania, Kriss LU orcid ; Carlsen, Jørn ; Hesselstrand, Roger LU ; Andréasson, Kristofer LU and Rådegran, Göran LU (2026) In Pulmonary Circulation 16(1).
Abstract

Patients with pulmonary arterial hypertension (PAH) experience long diagnostic delays, high functional class at diagnosis and poor prognosis. We aimed to study the differentiative and predictive value of 90 inflammatory and immunomodulatory related proteins in idiopathic and hereditary PAH (IPAH/HPAH) and systemic sclerosis-associated PAH (SSc-APAH). Cohort 1 comprised patients with SSc-APAH (
n  = 36), IPAH/HPAH (
n  = 54) and healthy controls (
n  = 55). Cohort 2 comprised SSc patients without PAH (
n  = 15) and SSc-APAH (
n  = 15), with blood samples both ~6 years before, and at PAH diagnosis. This cohort was used for internal validation and to predict future development of PAH in SSc. Cohort 3 comprised... (More)

Patients with pulmonary arterial hypertension (PAH) experience long diagnostic delays, high functional class at diagnosis and poor prognosis. We aimed to study the differentiative and predictive value of 90 inflammatory and immunomodulatory related proteins in idiopathic and hereditary PAH (IPAH/HPAH) and systemic sclerosis-associated PAH (SSc-APAH). Cohort 1 comprised patients with SSc-APAH (
n  = 36), IPAH/HPAH (
n  = 54) and healthy controls (
n  = 55). Cohort 2 comprised SSc patients without PAH (
n  = 15) and SSc-APAH (
n  = 15), with blood samples both ~6 years before, and at PAH diagnosis. This cohort was used for internal validation and to predict future development of PAH in SSc. Cohort 3 comprised connective tissue disease (CTD) APAH (
n  = 19) and IPAH (
n  = 20), and was used for external validation. Plasma protein levels were measured with proximity extension assay. In cohort 1, we found that higher IL-27 differentiated PAH patients from controls (odds ratio (OR) = 1.24; area under the curve (AUC) = 0.94), whereas higher TNFRSF4 differentiated SSc-APAH from IPAH/HPAH (OR = 1.14; AUC = 0.82), and controls (OR = 1.30; AUC = 0.99). In cohort 2, GDF-15 and PSP-D were higher in female SSc patients that would develop vs those that wouldn't develop PAH, and predicted PAH-development ~6 years before diagnosis (OR = 1.24; AUC = 0.78 and 1.22; 0.73, respectively). Using equivalence testing, levels of IL-27, GDF-15 and PSP-D were equivalent (
p  = 0.0072,
p  = 0.0048 and
p  = 0.00076) in cohort 3 and 1. In conclusion, GDF-15 and PSP-D emerged as promising potential biomarkers in early screening and prediction of future PAH development in SSc, whereas IL-27 and TNFRSF4 appeared promising in diagnosis and subtype differentiation of PAH and SSc-APAH.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pulmonary Circulation
volume
16
issue
1
article number
e70251
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105030713224
  • pmid:41727704
ISSN
2045-8932
DOI
10.1002/pul2.70251
language
English
LU publication?
yes
additional info
© 2026 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.
id
28b33999-2d6f-4c56-b73d-bb59ce1e2c60
date added to LUP
2026-03-01 08:00:23
date last changed
2026-03-30 10:51:27
@article{28b33999-2d6f-4c56-b73d-bb59ce1e2c60,
  abstract     = {{<p>Patients with pulmonary arterial hypertension (PAH) experience long diagnostic delays, high functional class at diagnosis and poor prognosis. We aimed to study the differentiative and predictive value of 90 inflammatory and immunomodulatory related proteins in idiopathic and hereditary PAH (IPAH/HPAH) and systemic sclerosis-associated PAH (SSc-APAH). Cohort 1 comprised patients with SSc-APAH (<br>
 n  = 36), IPAH/HPAH ( <br>
 n  = 54) and healthy controls ( <br>
 n  = 55). Cohort 2 comprised SSc patients without PAH ( <br>
 n  = 15) and SSc-APAH ( <br>
 n  = 15), with blood samples both ~6 years before, and at PAH diagnosis. This cohort was used for internal validation and to predict future development of PAH in SSc. Cohort 3 comprised connective tissue disease (CTD) APAH ( <br>
 n  = 19) and IPAH ( <br>
 n  = 20), and was used for external validation. Plasma protein levels were measured with proximity extension assay. In cohort 1, we found that higher IL-27 differentiated PAH patients from controls (odds ratio (OR) = 1.24; area under the curve (AUC) = 0.94), whereas higher TNFRSF4 differentiated SSc-APAH from IPAH/HPAH (OR = 1.14; AUC = 0.82), and controls (OR = 1.30; AUC = 0.99). In cohort 2, GDF-15 and PSP-D were higher in female SSc patients that would develop vs those that wouldn't develop PAH, and predicted PAH-development ~6 years before diagnosis (OR = 1.24; AUC = 0.78 and 1.22; 0.73, respectively). Using equivalence testing, levels of IL-27, GDF-15 and PSP-D were equivalent ( <br>
 p  = 0.0072, <br>
 p  = 0.0048 and <br>
 p  = 0.00076) in cohort 3 and 1. In conclusion, GDF-15 and PSP-D emerged as promising potential biomarkers in early screening and prediction of future PAH development in SSc, whereas IL-27 and TNFRSF4 appeared promising in diagnosis and subtype differentiation of PAH and SSc-APAH.<br>
 </p>}},
  author       = {{Engel Sällberg, Adam and Ahmed, Salaheldin and Ahmed, Abdulla and Kania, Kriss and Carlsen, Jørn and Hesselstrand, Roger and Andréasson, Kristofer and Rådegran, Göran}},
  issn         = {{2045-8932}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Pulmonary Circulation}},
  title        = {{Plasma GDF-15 and PSP-D Predict the Development of Pulmonary Arterial Hypertension in Systemic Sclerosis}},
  url          = {{http://dx.doi.org/10.1002/pul2.70251}},
  doi          = {{10.1002/pul2.70251}},
  volume       = {{16}},
  year         = {{2026}},
}