Frédéric Desmoulins

Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study

BACKGROUND Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögrens syndrome (pSS). OBJECTIVES To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. METHODS Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögrens syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. RESULTS Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögrens Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögrens Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmers test did not change. CONCLUSIONS These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

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

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.

Brief Report: Monoclonal Gammopathy and Risk of Lymphoma and Multiple Myeloma in Patients With Primary Sjögren's Syndrome.

To assess the link between monoclonal gammopathy (MG), disease activity, and incidence of malignant hematologic disorders (MHDs), including lymphoma and multiple myeloma (MM), in patients with primary Sjögrens syndrome (SS).

ACPA-positive primary Sjögren's syndrome: true primary or rheumatoid arthritis-associated Sjögren's syndrome?

Objectives Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5–10% of primary Sjögrens syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. Patients and methods ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria. Results At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5–10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA. Conclusions Median term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.

OP0113 Modification of Salivary Gland Lymphocyte Pattern after Belimumab in Primary Sjogren’s Syndrome: Results of the Beliss Study

Background The BAFF (or BLyS) cytokine plays a key role in pathogenesis of primary Sjogren’s syndrome (pSS). The level of BAFF is increased in the serum and BAFF may be expressed by salivary epithelial cells and the lymphoid infiltrate of salivary glands. Moreover, BAFF is induced by innate immunity stimulation, the later playing a role in pSS pathogenesis. Belimumab, the first biological treatment inhibiting soluble BAFF/BLyS has proved its effectiveness in systemic lupus and has been recently approved for this indication. Lupus and pSS share a lot of pathogenic mechanism including interferon signature and BAFF involvement. Thus we run the first open label study of belimumab in pSS patients and recently showed that 19/30 patients (63%) achieved the primary end-point which was a composite clinico-biological outcome. Objectives To address the change in labial salivary gland (LSG) inflammation after Belimumab therapy Methods Patients were included in 2 parallel and identical studies in 2 European Centres. Patients had to fulfill AECG criteria, to be anti-SSA/SSB positive and had to have at the time of inclusion either systemic complications or early disease (<5 yrs of symptoms), or the presence of biomarker of B-cell activation. The patients were treated with belimumab 10 mg/kg W0, W2, W4 and then every four weeks until W24. Minor labial salivary gland (LSG) biopsies of the 15 patients (all female, mean age=50 yrs, mean disease duration= 5 yrs) from the French center, performed at W0 and W28, were analyzed for estimating the focus score, the B-cell/T-cell ratio (CD20 and CD3 staining), BAFF expression (BAFF (Buffy-2) staining) and NK infiltrate (NKp46 staining). Results Before treatment, significant lymphocytic sialadenitis (focus score >1) was observed in 11 (78.6%) patients before treatment, five of whom became negative (focus score <1) at w28[51] (p=0.07). The median focus score decreased from 1.6 to 0.5 (p=0.39) and the median Chisholm score from 4 to 2 (p=0.01). B-cell /T cell ratio decreased after treatment in 5 patients and remained stable in all other patients (median ratio decreased from 0.58 to 0.50, p=0.055). Before treatment, a BAFF staining was detected in 11/14 (78.6%) patients, and in only 7/14 (50.0%) after belimumab (p=0.07). The median percentage of BAFF positive cells in foci significantly decreased from 27.5% to 5% after belimumab therapy (p=0.03). NKp46 staining revealed that NK cells infiltrate was predominantly located in interstitium rather than in foci (median number of NK cell: 24.7 vs. 8.2/mm², p=0.0003), and did not change after belimumab. Conclusions There was a clear tendency in favour of a decrease in foci number, B cells and BAFF-expressing cells within LSG after belimumab therapy. It is tempting to interpret the decrease in BAFF staining as an effect of the drug on membrane BAFF-expressing cells, but it could be also only due to the decrease in B cells expressing BAFF receptors linked to soluble BAFF passively stained by the anti-BAFF antibody. After belimumab therapy, we observed regression of lymphocytic infiltration of LSG in one third of the patients. Also the percentage of BAFF positive cells significantly decreased with a trend to a decrease of B-cell/T-cell ratio. Disclosure of Interest None Declared

THU0395 Low Numbers of Blood and Salivary Natural Killer Cells are Associated with a Better Response to Belimumab in Primary Sjogren's Syndrome: Results of the Beliss Study

Background The BAFF (or BLyS) cytokine plays a key role in pathogenesis of primary Sjogrens syndrome (pSS), thus testing belimumab (biological treatment inhibiting soluble BAFF/BLyS) in pSS patients, seems appealing. Clinical results of the BELISS study have been previously reported [1]. Objectives To address changes in blood lymphocyte sub-populations and labial salivary gland (LSG) inflammation after belimumab in patients with primary Sjögrens syndrome (pSS) and identify predictors of response to treatment.To address changes in blood lymphocyte sub-populations and labial salivary gland (LSG) inflammation after belimumab in patients with primary Sjögrens syndrome (pSS) and identify predictors of response to treatment. Methods Sequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 pSS patients (all females, median age =44 [36.5-63.5] years, median disease duration=1 [0.5-6.5] years) treated with belimumab. Systemic response to treatment was defined as a decrease of the ESSDAI ≥3 points at W28. Results After belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-IgD+ naïve B-cells (151 [24-186] at W0 vs 10 [6-40] at W28, p=0.008, n=9). No significant change in the total lymphocyte, total T-cell, CD4 or CD8 T-cell counts was observed. By contrast, there was a significant increase in the number of NK cells (p=0.032) Regarding histological pattern, lymphocytic sialadenitis (focus score >1) present in 12 (80.0%) patients before belimumab, became negative in 5 after treatment (p=0.03). The median LSG B-cell /T-cell ratio decreased from 0.58 [0.5-0.67] to 0.50 [0.5-0.5] (p=0.06). BAFF staining was detected in 11/14 (78.6%) patients, before, compared to 7/14 (50.0%) after belimumab (p=0.10). The median percentage of BAFF positive cells in foci significantly decreased from 27.5% [10-40] to 5% [0-20], after belimumab (p=0.03). Systemic response was obtained in 6 (40%) patients. The only predictor of response was the presence of a low number of 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. Conclusions Low blood and salivary NK cells numbers are associated with a better response to belimumab. This suggests that 2 distinct subsets of pSS may exist: one with predominant type-I INF/BAFF/B-cell axis, good responders to belimumab, and one with predominant type-II IFN/NK-cell axis, non-responders. References Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, et al. Efficacy and safety of belimumab in primary Sjogrens syndrome: results of the BELISS open-label phase II study. Annals of the rheumatic diseases. 2013. Disclosure of Interest None declared