Low NK cell levels aid PAH diagnosis in people with SSc: Study

Patients also had abnormal levels of heart damage marker BNP, uric acid
by Andrea Lobo, PhD | March 4, 2025

Low levels of a type of white blood cell called natural killer (NK) cells may help diagnose pulmonary arterial hypertension (PAH) in people with systemic sclerosis (SSc), a study in China suggests.

In PAH, the blood vessels that supply blood to the lungs, called pulmonary arteries, narrow, restricting blood flow and raising blood pressure. In the study, about 28% of the SSc patients had PAH.

Abnormal levels of BNP, a marker of heart damage, and of uric acid, which is an indicator of lower kidney function, were also evident in SSc-PAH patients.

“These indicators can aid in evaluating disease activity and pulmonary hypertension incidence in SSc,” wrote the researchers, who noted that while the markers have “clinical value for diagnosing PAH … their independent diagnostic utility for SSc-PAH remains suboptimal.” The study, “Natural killer cells are decreased in systemic sclerosis and have diagnostic value for pulmonary arterial hypertension incorporation,” was published in Scientific Reports.

SSc is marked by inflammation and fibrosis, or the accumulation of scar tissue, in the skin and even the internal organs, including the lungs. PAH is a leading cause of death in SSc, also called scleroderma.
​
The disease mechanisms involve autoimmune, or self-reactive, processes and abnormal inflammatory responses. Immune NK cells have been implicated in other autoimmune diseases and have shown alterations in people with SSc.

​Diagnosing SSc-PAH with NK cellsHere, researchers analyzed whether changes in immune cells and in some molecules they release could be associated with organ involvement in people with SSc. A total of 115 patients, with an average age at disease onset of 56.6 and mainly women, were included.

Most had diffuse cutaneous SSc (77.4%) and known SSc autoantibodies called antinuclear antibodies (90.4%). Almost half had active disease, defined as a European Scleroderma Study Group disease activity index (EScEG-AI) score higher than 3. Almost two-thirds had interstitial lung disease, which is a group of conditions marked by inflammation and scarring in the lungs, followed by digestive tract involvement (47%) and PAH (about 28%).

Compared with 100 age and sex-matched healthy people, SSc patients had lower counts, but a higher percentage of T-cells. Both the number and percentage of NK cells were significantly lower in patients, who also had higher levels of certain cytokines, small proteins cells use to communicate and help regulate processes like inflammation, including interleukin (IL)-2, IL-6, IL-10, and interferon-gamma.

An analysis showed that a lower NK cell percentage or count was associated with more severe skin involvement, assessed by the modified Rodnan Skin Score, and more severe organ damage in the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI).

SSc participants with PAH had a significantly longer SSc duration (11.9 vs. 5.6 years), higher organ damage (5 vs. 2 in the SCTC-DI score), and higher disease activity (5 vs. 3 in the EScEG-AI score), than those without PAH (82 patients). Also, SSc-PAH patients had significantly lower levels of NK cells than those without PAH and the healthy people.

They also had elevated BNP, of the inflammation markers C-reactive protein and erythrocyte sedimentation ratio, uric acid, and blood clotting markers. No differences were seen in cytokine levels between the two patient groups.

A further analysis showed blood levels of NK cells, uric acid, and BNP were independent risk factors for PAH in SSc patients.

The predictive value of these indicators for the diagnosis of SSc-related PAH was assessed using the ROC curve, a test that evaluates how well a measure can differentiate between people with or without a disease. Results showed the optimal cutoff for NK cells was 185 cells/microliter, below which patients are more likely to develop PAH. For BNP, a cutoff value of 70.5 picograms (pg)/mL was determined, while for uric acid the value was 323 umol/L. Patients with levels of BNP and uric acid above the cutoff were more likely to develop PAH.
​
“More comprehensive screening for SSc-PAH is necessary to confirm the diagnostic efficacy of novel markers and establish appropriate thresholds to enhance accuracy,” the researchers wrote. “Consequently, early intervention should be implemented to improve clinical prognosis before irreversible pathophysiological [disease-related] changes occur.”