Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjögren’s syndrome: results of the BELISS study

Abstract

IntroductionIn this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren’s syndrome (pSS) and to identify predictors of response to treatment.MethodsSequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index score of ≥3 points at W28.ResultsAfter belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D–positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5–0.67) to 0.50 (0.5–0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10–40) to 5 % (0–20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7–10] vs 11 % [9–21]; p=0.04) and in LSG (20.6/mm3 [20.0–21.4] vs 30.0/mm3 [25.0–100.0], p=0.003). Serum BAFF levels did not influence response to treatment.ConclusionsLow blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)–BAFF–B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN–NK cell axis, representing non-responders.Trial registrationClinicalTrials.gov identifier: NCT01160666. Registered 9 July 2010.

Role of the IL-12/IL-35 balance in patients with Sjögren syndrome

“…Finally, in the Belimumab in Subjects With Primary Sj€ ogren's Syndrome (BELISS) trial, good response was obtained exclusively in patients with low levels of natural killer cells in peripheral blood or the salivary glands. 44 These findings support the hypothesis of several forms of the disease. Patients with high levels of IL-12p70 in serum could have a T H 1 signature, have activation of natural killer cells both in blood and salivary glands, and be less sensitive to B cell-targeted therapy.…”

Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis

“…Increased BAFF serum levels also seem to be predictive of rituximab (RTX) treatment failure, suggesting a possible predictive role of BAFF serum levels in identifying a subset of patients suitable to be treated with this B-cell depleting agent [161]. On the contrary, data from a small open label study suggest that serum BAFF levels are not predictive for clinical to belimumab [162]. Although these results look very promising for personalised medicine, they have to be confirmed in larger cohorts before being helpful in daily clinical setting.…”

Do high numbers of salivary gland-infiltrating B cells predict better or worse outcomes after rituximab in patients with primary Sjögren's syndrome?

“…This debate is important and timely, since, besides its indisputable diagnostic value,3 salivary gland histopathology is increasingly considered to be a useful tool to assess the effects of treatments in clinical trials 4 5. Furthermore, despite promising open-labelled studies and two small randomised trials,6 the two large randomised controlled trials TEARS7 and TRACTISS8 (main results of which were revealed at the 2015 American College of Rheumatology meeting) did not demonstrate the superiority of rituximab over placebo on their primary end points.…”