Study suggests blood protein score may measure salivary gland inflammation in Sjögren’s disease

A newly identified Sjögren’s protein score, a blood protein signature of Sjögren’s disease, may help doctors measure inflammation inside the salivary glands without the need for a biopsy, a new study suggests. Results from the blood test, based on a group of 16 immune-related proteins, reflected local glandular inflammation and correlated with disease manifestations in other organs, genetic risk factors, and self-reactive antibodies associated with Sjögren’s.

Sjögren disease is a chronic autoimmune condition driven by immune-mediated injury to exocrine glands, most commonly presenting with sicca symptoms such as dry eyes and dry mouth. While dryness is often the most visible feature at presentation, Sjögren disease extends beyond glandular involvement and may affect multiple organ systems over time, including the joints, lungs, skin, kidneys, and peripheral nerves. Sjögren’s is also associated with reduced quality of life and an elevated risk of lymphoma.

The study, published in Annals of the Rheumatic Diseases, evaluated paired salivary gland biopsy samples and blood samples from 81 adults with Sjögren’s and 19 age- and sex-matched individuals with sicca but without Sjögren’s. The analysis of paired samples revealed more pronounced differences in salivary gland tissue than in blood between Sjögren’s patients and healthy controls. Several proteins were found at particularly high levels in the glands of Sjögren’s patients, including CXCL13, while other inflammation-related proteins, including CXCL10, were significantly elevated in both blood and gland tissue from patients compared with controls.

To confirm these findings, researchers analyzed blood samples from a discovery group comprising 456 adults with Sjögren’s and 141 healthy controls, and a replication group of 233 Sjögren’s patients and 137 controls. They found 27 proteins at significantly different levels in the blood of Sjögren’s patients compared with controls, and 16 of these were validated in the replication group. The most significant protein changes involved Gal9, CXCL13, PDCD1, CCL19, and LAG3.

Analyses of links between these proteins and extraglandular manifestations showed that higher blood CXCL10 levels were associated with swollen lymph nodes, skin symptoms, biological abnormalities, lung involvement, and lymphoma. Elevated CD8A and CD27 were linked to kidney involvement alone, while higher LAG3 was associated with more biological abnormalities. Those with lung involvement showed increases in many inflammation-related proteins, and all proteins related to lymphoma were also tied to lung involvement.

When patients were grouped based on the presence of self-reactive antibodies frequently associated with Sjögren’s, such as ANA, anti-Ro (SS-A), and anti-La (SS-B), blood levels of the validated 16 proteins increased gradually across these groups. They were lowest in people without ANA antibodies, higher in ANA-positive patients, and highest in those who were double-positive for SS-A and SS-B. A similar pattern was seen in salivary gland tissue, and blood levels of certain proteins closely matched those in gland tissue, with CD33 showing the strongest association, followed by LAIR2.

The findings come amid continuing need for reliable biomarkers in a disease in which sicca symptoms are often the initial presentation but reflect an underlying systemic autoimmune process. In addition to symptom burden, inadequately managed sicca can lead to clinically significant complications, including infections, dental disease, and chronic ocular surface damage. At present, management remains largely symptomatic, as no disease-modifying therapies are specifically approved for Sjögren disease, although emerging therapies targeting key immune pathways, including B cell-directed agents such as ianalumab, are under investigation.