Parotid salivary sodium levels of Sjögren's syndrome patients suggest B-cell mediated epithelial sodium channel disruption.

Patients with primary Sjögren's syndrome (SS) suffer widely from lack of saliva production. Here we investigate potential mechanisms underpinning changes in SS patient saliva composition. Sodium concentration was significantly higher in all saliva samples collected: unstimulated submandibular/sublingual (SmSl) saliva (p<0.0001), stimulated SmSl saliva (p=0.002) and stimulated parotid (PG) (p<0.0001) saliva, compared to non-SS sicca controls. Chloride, phosphate and potassium ion concentrations, α-amylase activity and total protein content correlations were less consistently changed between SS and non-SS saliva types. Stimulated PG salivary sodium levels correlated with the degree of CD45+ lymphocytic cell infiltrate in the parotid glands (r=0.69, p<0.001), and even more strongly so with infiltrating CD20+ B cells (r=0.73, p<0.0001). CD3+ T cells were only moderately correlated with salivary sodium (r=0.23, p=0.015). In non-SS control or focus score (FS) negative SS PG tissue, the epithelial sodium channel (ENaC), responsible for sodium transport out of saliva, was localised to the apical membrane of luminal striated duct cells. In PG tissue from FS+ SS patients, apical ENaC expression appeared absent. We hypothesise that B cell-related proinflammatory cytokines in SS salivary glands may dysregulate sodium transport channels in SS.

Abatacept treatment for patients with early active primary Sjögren's syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study).

BACKGROUND: Several small open-label studies have suggested efficacy of abatacept-a co-stimulation inhibitor-in patients with primary Sjögren's syndrome. These promising results warranted further evaluation. We therefore aimed to further assess the safety and efficacy of abatacept compared with placebo in patients with primary Sjögren's syndrome. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial at the University Medical Center Groningen (Groningen, Netherlands). We included patients with primary Sjögren's syndrome fulfilling the American-European Consensus Group criteria, aged 18 years or older, with positive salivary gland biopsies, time from diagnosis of 7 years or less, and a European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or more. Independent pharmacists randomly allocated patients (1:1) to either the abatacept group or placebo group using a computer-generated sequence stratified by previous use of disease-modifying anti-rheumatic drugs. Patients received at-home subcutaneous injections of abatacept (125 mg) or placebo once a week for 24 weeks. The primary outcome was the between-group difference in ESSDAI score at week 24. Efficacy was analysed in patients who received at least one drug dose and for whom post-baseline data were collected. Safety was analysed in all patients who received at least one drug dose. FINDINGS: Between Aug 14, 2014, and Aug 23, 2018, 580 patients were reviewed for eligibility, of which 80 patients were randomly assigned to receive study treatment. Efficacy was analysed in 40 patients receiving abatacept and 39 patients receiving placebo (one patient in this group was lost to follow-up). The primary outcome did not significantly differ between the treatment groups. The adjusted mean difference in ESSDAI score at week 24 between the abatacept group and placebo group was -1·3 (95% CI -4·1 to 1·6). No deaths or treatment-related serious adverse events occurred. In 38 (95%) of 40 patients in the abatacept group, 103 adverse events occurred, including one serious adverse event and 46 infections. In 38 (95%) of 40 patients in the placebo group, 87 adverse events occurred, including four serious adverse events and 49 infections. INTERPRETATION: On the basis of this trial, we cannot recommend abatacept treatment as standard of care to reduce systemic disease activity in patients with primary Sjögren's syndrome. Further studies should evaluate whether patients with specific clinical manifestations and biological characteristics might benefit from abatacept treatment. FUNDING: Bristol-Myers Squibb.

Regeneration of irradiated salivary glands with stem cell marker expressing cells.

BACKGROUND: Stem cell therapy could be a potential way for reducing radiation-induced hyposalivation and improving the patient's quality of life. However, the identification and purification of salivary gland stem cells have not been accomplished. This study aims to better characterize the stem/progenitor cell population with regenerative potential residing in the mouse salivary gland. METHODS: Mouse submandibular gland tissue, isolated cells and cultured 3 day old salispheres were tested for their expression of stem cell markers c-Kit, CD133, CD49f, and CD24 using immunohistochemistry for tissue and flow cytometry for cells. Mice were locally irradiated with a single dose of 15 Gy and transplanted with cells expressing defined markers. RESULTS: Cells expressing known stem cell markers are localized in the larger ducts of the mouse salivary gland. Isolated cells and cells from day 3 salispheres also express these markers: c-Kit (0.058% vs. 0.65%), CD133 (6% vs. 5%), CD49f (78% vs. 51%), and CD24 (60% vs. 60%, respectively). Intraglandular transplantation of these cells into irradiated salivary glands of mice resulted in stem cell marker-specific recovery of salivary gland function. CONCLUSIONS: Different stem cell-associated markers are expressed in mouse salivary gland cells, which upon transplantation are able to regenerate the irradiation damaged salivary gland.