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

Raphaèle Seror, Gaétane Nocturne, Thierry Lazure, Houria Hendel-Chavez, Frédéric Desmoulins, Rakiba Belkhir, Philippe Ravaud, Mohcine Benbijja, Vichnou Poirier-Colame, Yacine Taoufik, Xavier Mariette, Raphaèle Seror, Gaétane Nocturne, Thierry Lazure, Houria Hendel-Chavez, Frédéric Desmoulins, Rakiba Belkhir, Philippe Ravaud, Mohcine Benbijja, Vichnou Poirier-Colame, Yacine Taoufik, Xavier Mariette

Abstract

Introduction: 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.

Trial registration: ClinicalTrials.gov identifier: NCT01160666 . Registered 9 July 2010.

Figures

Fig. 1
Fig. 1
Changes in T, B and natural killer (NK) cell counts and B-cell subtypes after belimumab therapy. *p<0.05. W week
Fig. 2
Fig. 2
Changes in natural killer (NK) cell count and proportion in responders and non-responders. Number (upper plot) and percentage (lower plot) of NK cells in responders and non-responders are shown. *p<0.05
Fig. 3
Fig. 3
Changes in histological pattern of salivary glands after belimumab therapy. Regression of lymphocytic infiltration after belimumab therapy (a before and b after; hematein-eosin-saffron stain; original magnification, ×125), major decrease of B-cell activating factor expression (c before and d after; Buffy-2 immunohistochemical stain, original magnification, ×320.), dramatic decrease of B-cell infiltration (e before and f after; CD20 immunohistochemical stain; original magnification, ×250), with slight decrease or stability of T-cell infiltration (g before and h after; CD3 immunohistochemical stain; original magnification, ×250), resulting in a trend for a decrease in B-cell/T-cell ratio

References

    1. Tzioufas AG, Vlachoyiannopoulos PG. Sjogren’s syndrome: an update on clinical, basic and diagnostic therapeutic aspects. J Autoimmun. 2012;39:1–3. doi: 10.1016/j.jaut.2012.01.006.
    1. García-Carrasco M, Ramos-Casals M, Rosas J, Pallarés L, Calvo-Alen J, Cervera R, et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002;81:270–80. doi: 10.1097/00005792-200207000-00003.
    1. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56. doi: 10.1084/jem.189.11.1747.
    1. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–710. doi: 10.1084/jem.190.11.1697.
    1. Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Xu D, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 2003;48:3475–86. doi: 10.1002/art.11354.
    1. Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis. 2003;62:168–71. doi: 10.1136/ard.62.2.168.
    1. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58:2453–9. doi: 10.1002/art.23678.
    1. Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 2013;65:2672–9.
    1. Gottenberg JE, Seror R, Miceli-Richard C, Benessiano J, Devauchelle-Pensec V, Dieude P, et al. Serum levels of β2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren’s syndrome: data at enrollment in the prospective ASSESS cohort. PLoS One. 2013;8:e59868. doi: 10.1371/journal.pone.0059868.
    1. Quartuccio L, Salvin S, Fabris M, Maset M, Pontarini E, Isola M, et al. BLyS upregulation in Sjögren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford) 2013;52:276–81. doi: 10.1093/rheumatology/kes180.
    1. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, randomised, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918–30. doi: 10.1002/art.30613.
    1. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–31. doi: 10.1016/S0140-6736(10)61354-2.
    1. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–8. doi: 10.1136/ard.61.6.554.
    1. Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, et al. Efficacy and safety of belimumab in primary Sjögren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74:526–31. doi: 10.1136/annrheumdis-2013-203991.
    1. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al. EULAR Sjögren’s Syndrome Disease Activity Index: development of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum Dis. 2010;69:1103–9. doi: 10.1136/ard.2009.110619.
    1. Seror R, Bootsma H, Saraux A, Bowman SJ, Theander E, Brun JG, et al. Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum Dis. 2014 [Epub ahead of print] PubMed PMID: 25480887. doi:10.1136/annrheumdis-2014-206008.
    1. Rusakiewicz S, Nocturne G, Lazure T, Semeraro M, Flament C, Caillat-Zucman S, et al. NCR3/NKp30 contributes to pathogenesis in primary Sjögren’s syndrome. Sci Transl Med. 2013;5:195ra196.
    1. Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64:2328–37. doi: 10.1002/art.34400.
    1. Jacobi AM, Huang W, Wang T, Freimuth W, Sanz I, Furie R, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2010;62:201–10. doi: 10.1002/art.27189.
    1. Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum. 2002;46:2160–71. doi: 10.1002/art.10445.
    1. Badr G, Borhis G, Lefevre EA, Chaoul N, Deshayes F, Dessirier V, et al. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells. Blood. 2008;111:2744–54. doi: 10.1182/blood-2007-03-081232.
    1. Daridon C, Devauchelle V, Hutin P, Le Berre R, Martins-Carvalho C, Bendaoud B, et al. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjögren’s syndrome. Arthritis Rheum. 2007;56:1134–44. doi: 10.1002/art.22458.
    1. Lavie F, Miceli-Richard C, Ittah M, Sellam J, Gottenberg JE, Mariette X. B-cell activating factor of the tumour necrosis factor family expression in blood monocytes and T cells from patients with primary Sjögren’s syndrome. Scand J Immunol. 2008;67:185–92. doi: 10.1111/j.1365-3083.2007.02049.x.
    1. Hall JC, Casciola-Rosen L, Berger AE, Kapsogeorgou EK, Cheadle C, Tzioufas AG, et al. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A. 2012;109:17609–14. doi: 10.1073/pnas.1209724109.
    1. Ittah M, Miceli-Richard C, Gottenberg JE, Sellam J, Eid P, Lebon P, et al. Viruses induce high expression of BAFF by salivary gland epithelial cells through TLR- and type-I IFN-dependent and -independent pathways. Eur J Immunol. 2008;38:1058–64. doi: 10.1002/eji.200738013.
    1. Ittah M, Miceli-Richard C, Gottenberg JE, Lavie F, Lazure T, Ba N, et al. B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren’s syndrome. Arthritis Res Ther. 2006;8:R51. doi: 10.1186/ar1912.
    1. Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren’s syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis. 2013;72:728–35. doi: 10.1136/annrheumdis-2012-201381.
    1. Emamian ES, Leon JM, Lessard CJ, Grandits M, Baechler EC, Gaffney PM, et al. Peripheral blood gene expression profiling in Sjögren’s syndrome. Genes Immun. 2009;10:285–96. doi: 10.1038/gene.2009.20.
    1. Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjögren’s syndrome. Nat Rev Rheumatol. 2013;9:544–56. doi: 10.1038/nrrheum.2013.110.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅