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.
BACKGROUND
In 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.


METHODS
Sequential 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.


RESULTS
After 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/mm(3) [20.0-21.4] vs 30.0/mm(3) [25.0-100.0], p=0.003). Serum BAFF levels did not influence response to treatment.


CONCLUSIONS
Low 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.


BACKGROUND
ClinicalTrials.gov identifier: NCT01160666 . Registered 9 July 2010.
Université Paris-Sud, Center of Research on Immunology of Viral and Autoimmune diseases (IMVA), INSERM U1184, Le Kremlin Bicêtre, France. raphaele.se@gmail.com.|Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France. raphaele.se@gmail.com.
Raphaèle
R
Seror
Université Paris-Sud, Center of Research on Immunology of Viral and Autoimmune diseases (IMVA), INSERM U1184, Le Kremlin Bicêtre, France. gaetanenocturne@gmail.com.
Gaétane
G
Nocturne
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'anatomopathologie, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. Thierry.lazure@aphp.fr.
Thierry
T
Lazure
Université Paris-Sud, Center of Research on Immunology of Viral and Autoimmune diseases (IMVA), INSERM U1184, Le Kremlin Bicêtre, France. houria.chavez@aphp.fr.|Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'immunologie, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. houria.chavez@aphp.fr.
Houria
H
Hendel-Chavez
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France. frederic.desmoulins@aphp.fr.
Frédéric
F
Desmoulins
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France. rakiba.belkhir@aphp.fr.
Rakiba
R
Belkhir
Université Paris Descartes, AP-HP, Hôtel-Dieu Hospital, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS-UMR1153), Paris, France. philippe.ravaud@aphp.fr.
Philippe
P
Ravaud
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France. mohcine.benbijja@gmail.com.
Mohcine
M
Benbijja
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), INSERM U1015, GRCC, 475 rur Edouard Vaillant, 94805, Villejuif, France. Vichnou.poiriercolame@igr.fr.
Vichnou
V
Poirier-Colame
Université Paris-Sud, Center of Research on Immunology of Viral and Autoimmune diseases (IMVA), INSERM U1184, Le Kremlin Bicêtre, France. yacine.taoufik@aphp.fr.|Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'immunologie, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. yacine.taoufik@aphp.fr.
Yacine
Y
Taoufik
Université Paris-Sud, Center of Research on Immunology of Viral and Autoimmune diseases (IMVA), INSERM U1184, Le Kremlin Bicêtre, France. xavier.mariette@bct.aphp.fr.|Université Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France. xavier.mariette@bct.aphp.fr.
Xavier
X
Mariette
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000378:metabolism*; D018655:Lymphocyte Count; D008875:Middle Aged; D012470:Salivary Glands, Minor / Q000378:metabolism* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; D007166:Immunosuppressive Agents; C505719:TNFSF13B protein, human; C511911:belimumab