Cytokine Profiles May Signal High Risk of PAH in Patients With Systemic Sclerosis

Cytokine profiles could be an effective tool to identify which patients with systemic sclerosis (SSc) are at highest risk of pulmonary arterial hypertension (PAH), according to a new study.

The findings, published in Arthritis Research & Therapy, show that patients with PAH or who were considered to be at high risk of PHA had notably different cytokine profiles compared with patients at low risk for PAH and healthy controls.

The authors explained that PAH affects an 8% to 12% of patients with SSc and is a leading cause of death within that patient group.

The investigators said an increasing body of evidence supports the idea that early PAH-focused intervention can improve survival and functional status in patients with SSc. However, it can be difficult to accurately identify high-risk patients. Although right heart catheterization is the most accurate option, it is not ideal due to its invasive nature. Other algorithms have been proposed to screen patients with SSc, but the investigators said such algorithms lack the specificity required to be a first-line screening tool.

Lorinda Chung, MD, MS, of the Stanford University School of Medicine, and colleagues said an emerging biomarker in this patient group is cytokine profiles.

“Previous studies have detected changes in expression of individual cytokines involved in vascular injury and inflammation in patients with SSc-PAH compared to healthy controls and patients with SSc and no PAH,” the authors wrote, citing the inflammatory mediators TNF-alpha, interleukin-1β, intercellular adhesion molecule 1, and IL-6, along with vascular-injury markers vascular cell adhesion molecule 1, vascular endothelial growth factor (VEGF), and von Willebrand factor, as potentially useful biomarkers.

The authors decided to see whether they could identify cytokine profiles that might align with a high risk of PAH. They used a multicenter prospective registry to identify 71 patients at high risk of PAH, 81 patients with incident PAH based on right heart catheterization, 10 patients with SSc who were considered low risk due to normal pulmonary function tests and echocardiogram parameters, and 20 healthy controls.

The investigators then used custom 14- and 65-plex arrays to analyze patients’ cytokine expression and compared the results using principal component analysis and Tukey’s test results. The results, which the authors described as exploratory in nature, showed each patient group had unique cytokine clustering.

“Overall, there was very little difference in cytokine expression comparing high-risk and PAH patient groups; however, these groups had substantially different cytokine profiles compared to low-risk patients and [healthy controls],” they wrote, adding that the apparent similarity between patients with PAH and those at high risk suggests that there is a disease continuum for PAH.

The investigators said their research found pro-inflammatory cytokines including regulated upon activation, normal t cell expressed and presumably secreted (or RANTES); interleukin-12p40; and interferon-βwere elevated in all patients with SSc, “but most prominently in patients on the PAH spectrum when compared to healthy controls.”

In addition, they said the high-risk and PAH groups also had significantly increased levels of VEGF-D compared to the low-risk and healthy control groups.

The authors said their study suggests cytokine profiles could be helpful to both physicians and drug developers.

“We anticipate these data could be used to risk stratify SSc patients and guide therapy,” they concluded. “These data may provide potential mechanistic targets to increase our understanding of SSc-PAH and support therapeutic innovation in the future.”

Reference

Kolstad KD, Khatri A, Donato M, et al. Cytokine signatures differentiate systemic sclerosis patients at high versus low risk for pulmonary arterial hypertension. Arthritis Res Ther. Published online February 9, 2022. doi:10.1186/s13075-022-02734-9