Characterization of B- and T-Cell Compartment and B-Cell Related Factors Belonging to the TNF/TNFR Superfamily in Patients With Clinically Active Systemic Lupus Erythematosus: Baseline BAFF Serum Levels Are the Strongest Predictor of Response to Belimumab after Twelve Months of Therapy

Silvia Piantoni, Francesca Regola, Stefania Masneri, Michele Merletti, Torsten Lowin, Paolo Airò, Angela Tincani, Franco Franceschini, Laura Andreoli, Georg Pongratz, Silvia Piantoni, Francesca Regola, Stefania Masneri, Michele Merletti, Torsten Lowin, Paolo Airò, Angela Tincani, Franco Franceschini, Laura Andreoli, Georg Pongratz

Abstract

Background: Patients with systemic lupus erythematosus (SLE) show increased serum levels of tumor necrosis factor (TNF)/TNF receptor (R) superfamily member, e.g. BAFF (B lymphocyte stimulator). Belimumab, a monoclonal antibody against soluble BAFF, is used for treatment of SLE. Although B cells are the main target, a BAFF-dependent T-cell activation pathway also plays a role. High levels of anti-DNA antibodies and low complement at baseline are known predictors of response to Belimumab. Objectives: To explore the association of circulating lymphocytes and serum levels of B- cell related TNF/TNFR superfamily members with response to Belimumab in SLE patients. Methods: Twenty-one SLE patients received Belimumab. Clinical evaluation and laboratory tests were performed at baseline, at 6 and 12 months. TNF super-family members (BAFF, APRIL, sBCMA, sCD40L, sTACI, TWEAK) were tested by high-sensitivity ELISA in all patients, and lymphocyte immunophenotyping was performed by flow cytometry in ten subjects. SLE-disease activity was assessed by SLEDAI-2K score. Linear regression modeling was used to investigate parameters influencing SLEDAI-2K and anti-dsDNA antibody titers over time and for predictive models. Results: Clinical improvement was observed in all patients. A global reduction of circulating B cells, especially naïve, was detected, without variation in the T-cell compartment. All TNF family members decreased, whereas APRIL remained constant. The increase in serum levels of C3 (p = 0.0004) and sTACI (p = 0.0285) was associated with a decrease of SLEDAI-2K. The increase of C4 (p = 0.027) and sBCMA (p = 0.0015) and the increase of CD8+ T cells (p = 0.0160) were associated with a decrease, whereas an increase of sCD40L in serum (p = 0.0018) and increased number of CD4+ T cells (p = 0.0029) were associated with an increase, in anti-dsDNA antibody titers, respectively. Using stepwise forward inclusion, the minimal model to predict SLEDAI-2K response at 12 months included BAFF (p = 3.0e - 07) and SLEDAI-2K (p = 7.0e - 04) at baseline. Baseline APRIL levels also showed an association, although the overall model fit was weaker. Conclusion: In our real-life cohort, baseline serum levels of BAFF were the best predictor of response to Belimumab, confirming post-hoc results of the BLISS study and suggesting the utility of this particular biomarker for the identification of patients who are more likely to respond.

Keywords: TNF/TNFR superfamily-related factors; adaptive immunity; belimumab; biomarkers; systemic lupus erythematosus.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Piantoni, Regola, Masneri, Merletti, Lowin, Airò, Tincani, Franceschini, Andreoli and Pongratz.

Figures

FIGURE 1
FIGURE 1
Serological levels of the TNF Superfamily members at different time points in each subject. BAFF, B cell activating factor; APRIL, a proliferation-inducing ligand; sTACI, soluble transmembrane activator and calcium-modulator and cyclophilin ligand interactor; sBCMA, soluble B cell maturation antigen; sCD40L, soluble CD40 ligand; TWEAK, TNF-related weak inducer of apoptosis.

References

    1. Basso K., Klein U., Niu H., Stolovitzky G. A., Tu Y., Califano A., et al. (2004). Tracking CD40 Signaling during Germinal Center Development. Blood. 104 (13), 4088–4096. 10.1182/blood-2003-12-4291
    1. Belnoue E., Pihlgren M., McGaha T. L., Tougne C., Rochat A.-F., Bossen C., et al. (2008). APRIL Is Critical for Plasmablast Survival in the Bone Marrow and Poorly Expressed by Early-Life Bone Marrow Stromal Cells. Blood 111 (5), 2755–2764. 10.1182/blood-2007-09-110858
    1. Burkly L. C. (2014). TWEAK/Fn14 axis: the Current Paradigm of Tissue Injury-Inducible Function in the Midst of Complexities. Semin. Immunol. 26 (3), 229–236. 10.1016/j.smim.2014.02.006
    1. Coquery C. M., Loo W. M., Wade N. S., Bederman A. G., Tung K. S., Lewis J. E., et al. (2015). BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon-γ Production in Autoimmunity. Arthritis Rheumatol. 67 (3), 773–784. 10.1002/art.38950
    1. Darce J. R., Arendt B. K., Wu X., Jelinek D. F. (2007). Regulated Expression of BAFF-Binding Receptors during Human B Cell Differentiation. J. Immunol. 179 (11), 7276–7286. 10.4049/jimmunol.179.11.7276
    1. Dooley M. A., Houssiau F., Aranow C., D'Cruz D. P., Askanase A., Roth D. A., et al. (2013). Effect of Belimumab Treatment on Renal Outcomes: Results from the Phase 3 Belimumab Clinical Trials in Patients with SLE. Lupus. 22, 63–72. 10.1177/0961203312465781
    1. Furie R., Petri M., Zamani O., Cervera R., Wallace D. J., Tegzová D., et al. (2011). A Phase III, Randomized, Placebo-Controlled Study of Belimumab, a Monoclonal Antibody that Inhibits B Lymphocyte Stimulator, in Patients with Systemic Lupus Erythematosus. Arthritis Rheum. 63, 3918–3930. 10.1002/art.30613
    1. Gordon C., Sutcliffe N., Skan J., Stoll T., Isenberg D. A. (2003). Definition and Treatment of Lupus Flares Measured by the BILAG Index. Rheumatology. 42 (11), 1372–1379. 10.1093/rheumatology/keg382
    1. Grewal I. S., Flavell R. A. (1996). The Role of CD40 Ligand in Costimulation and T-Cell Activation. Immunol. Rev. 153, 85–106. 10.1111/j.1600-065x.1996.tb00921.x
    1. He B., Santamaria R., Xu W., Cols M., Chen K., Puga I., et al. (2010). The Transmembrane Activator TACI Triggers Immunoglobulin Class Switching by Activating B Cells through the Adaptor MyD88. Nat. Immunol. 11 (9), 836–845. 10.1038/ni.1914
    1. Hochberg M. C. (1997). Updating the American College of Rheumatology Revised Criteria for the Classification of Systemic Lupus Erythematosus. Arthritis Rheum. 40 (9), 1725. 10.1002/art.1780400928
    1. Hoffmann F. S., Kuhn P. H., Laurent S. A., Hauck S. M., Berer K., Wendlinger S. A., et al. (2015). The Immunoregulator Soluble TACI Is Released by ADAM10 and Reflects B Cell Activation in Autoimmunity. J. Immunol. 194 (2), 542–552. 10.4049/jimmunol.1402070
    1. Isenberg D., Gordon C., Licu D., Copt S., Rossi C. P., Wofsy D. (2015). Efficacy and Safety of Atacicept for Prevention of Flares in Patients with Moderate-To-Severe Systemic Lupus Erythematosus (SLE): 52-week Data (APRIL-SLE Randomised Trial). Ann. Rheum. Dis. 74 (11), 2006–2015. 10.1136/annrheumdis-2013-205067
    1. Kalled S. L., Cutler A. H., Datta S. K., Thomas D. W. (1998). Anti-CD40 Ligand Antibody Treatment of SNF1 Mice with Established Nephritis:preservation of Kidney Function. J. Immunol. 160, 2158–2165.
    1. Kang S., Fedoriw Y., Brenneman E. K., Truong Y. K., Kikly K., Vilen B. J. (2017). BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis. J. Immunol. 198, 2602–2611. 10.4049/jimmunol.1600281
    1. Koller M. (2016). Robustlmm: An R Package for Robust Estimation of Linear Mixed-Effects Models. J. Stat. Softw. 75 (6), 1–24. 10.18637/jss.v075.i06
    1. Koyama T., Tsukamoto H., Miyagi Y., Himeji D., Otsuka J., Miyagawa H., et al. (2005). Raised Serum APRIL Levels in Patients with Systemic Lupus Erythematosus. Ann. Rheum. Dis. 64 (7), 1065–1067. 10.1136/ard.2004.022491
    1. Laurent S. A., Hoffmann F. S., Kuhn P. H., Cheng Q., Chu Y., Schmidt-Supprian M., et al. (2015). γ-Secretase Directly Sheds the Survival Receptor BCMA from Plasma Cells. Nat. Commun. 11 (6), 7333. 10.1038/ncomms8333
    1. Lesley R., Xu Y., Kalled S. L., Hess D. M., Schwab S. R., Shu H. B., et al. (2004). Reduced Competitiveness of Autoantigen-Engaged B Cells Due to Increased Dependence on BAFF. Immunity. 20 (4), 441–453. 10.1016/s1074-7613(04)00079-2
    1. Meinl E., Thaler F. S., Lichtenthaler S. F. (2018). Shedding of BAFF/APRIL Receptors Controls B Cells. Trends Immunol. 39 (9), 673–676. 10.1016/j.it.2018.07.002
    1. Morel J., Roubille C., Planelles L., Rocha C., Fernandez L., Lukas C., et al. (2009). Serum Levels of Tumour Necrosis Factor Family Members a Proliferation-Inducing Ligand (APRIL) and B Lymphocyte Stimulator (BLyS) Are Inversely Correlated in Systemic Lupus Erythematosus. Ann. Rheum. Dis. 68 (6), 997–1002. 10.1136/ard.2008.090928
    1. Nagy G., Koncz A., Perl A. (2005). T- and B-Cell Abnormalities in Systemic Lupus Erythematosus. Crit. Rev. Immunol. 25 (2), 123–140. 10.1615/critrevimmunol.v25.i2.30
    1. Navarra S. V., Guzmán R. M., Gallacher A. E., Hall S., Levy R. A., Jimenez R. E., et al. (2011). Efficacy and Safety of Belimumab in Patients with Active Systemic Lupus Erythematosus: a Randomised, Placebo-Controlled, Phase 3 Trial. Lancet. 377, 721–723. 10.1016/S0140-6736(10)61354-2
    1. Ng L. G., Sutherland A. P. R., Newton R., Qian F., Cachero T. G., Scott M. L., et al. (2004). B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells. J. Immunol. 173 (2), 807–817. 10.4049/jimmunol.173.2.807
    1. O’Connor B. P., Raman V. S., Erickson L. D., Cook W. J., Weaver L. K., Ahonen C., et al. (2004). BCMA Is Essential for the Survival of Long-Lived Bone Marrow Plasma Cells. J. Exp. Med. 199 (1), 91–98. 10.1084/jem.20031330
    1. Parodis I., Sjöwall C., Jönsen A., Ramsköld D., Zickert A., Frodlund M., et al. (2017). Smoking and Pre-existing Organ Damage Reduce the Efficacy of Belimumab in Systemic Lupus Erythematosus. Autoimmun. Rev. 16 (4), 343–351. 10.1016/j.autrev.2017.02.005
    1. Peters A. L., Stunz L. L., Bishop G. A. (2009). CD40 and Autoimmunity: the Dark Side of a Great Activator. Semin. Immunol. 21 (5), 293–300. 10.1016/j.smim.2009.05.012
    1. Petri M., Stohl W., Chatham W., McCune W. J., Chevrier M., Ryel J., et al. (2008). Association of Plasma B Lymphocyte Stimulator Levels and Disease Activity in Systemic Lupus Erythematosus. Arthritis Rheum. 58 (8), 2453–2459. 10.1002/art.23678
    1. Petri M. A., van Vollenhoven R. F., Buyon J., Levy R. A., Navarra S. V., Cervera R., et al. (2013). Baseline Predictors of Systemic Lupus Erythematosus Flares: Data from the Combined Placebo Groups in the Phase III Belimumab Trials. Arthritis Rheum. 65 (8), 2143–2153. 10.1002/art.37995
    1. Piantoni S., Regola F., Zanola A., Andreoli L., Dall’Ara F., Tincani A., et al. (2018). Effector T-Cells Are Expanded in Systemic Lupus Erythematosus Patients with High Disease Activity and Damage Indexes. Lupus. 27, 143–149. 10.1177/0961203317722848
    1. Ramsköld D., Parodis I., Lakshmikanth T., Sippl N., Khademi M., Chen Y., et al. (2019). B Cell Alterations during BAFF Inhibition with Belimumab in SLE. EBioMedicine. 40, 517–527. 10.1016/j.ebiom.2018.12.035
    1. Regola F., Piantoni S., Lowin T., Archetti S., Reggia R., Kumar R., et al. (2019). Association between Changes in BLyS Levels and the Composition of B and T Cell Compartments in Patients with Refractory Systemic Lupus Erythematosus Treated with Belimumab. Front. Pharmacol. 10, 433. 10.3389/fphar.2019.00433
    1. Romero-Diaz J., Isenberg D., Ramsey-Goldman R. (2011). Measures of Adult Systemic Lupus Erythematosus: Updated Version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis Care Res. 11 (63 Suppl. 0 11), S37–S46. 10.1002/acr.20572
    1. Roth D. A., Thompson A., Tang Y., Hammer A. E., Molta C. T., Gordon D. (2016). Elevated BLyS Levels in Patients with Systemic Lupus Erythematosus: Associated Factors and Responses to Belimumab. Lupus. 25 (4), 346–354. 10.1177/0961203315604909
    1. Ruiz-Irastorza G., Bertsias G. (2020). Treating Systemic Lupus Erythematosus in the 21st Century: New Drugs and New Perspectives on Old Drugs. Rheumatology. 59 (Suppl. l), v69–v81. 10.1093/rheumatology/keaa403
    1. Salazar-Camarena D. C., Ortiz-Lazareno P. C., Cruz A., Oregon-Romero E., Machado-Contreras J. R., Muñoz-Valle J. F., et al. (2016). Association of BAFF, APRIL Serum Levels, BAFF-R, TACI and BCMA Expression on Peripheral B-Cell Subsets with Clinical Manifestations in Systemic Lupus Erythematosus. Lupus. 25 (6), 582–592. 10.1177/0961203315608254
    1. Salazar-Camarena D. C., Palafox-Sánchez C. A., Cruz A., Marín-Rosales M., Muñoz-Valle J. F. (2020). Analysis of the Receptor BCMA as a Biomarker in Systemic Lupus Erythematosus Patients. Sci. Rep. 10 (1), 6236. 10.1038/s41598-020-63390-0
    1. Samy E., Wax S., Huard B., Hess H., Schneider P. (2017). Targeting BAFF and APRIL in Systemic Lupus Erythematosus and Other Antibody-Associated Diseases. Int. Rev. Immunol. 36 (1), 3–19. 10.1080/08830185.2016.1276903
    1. Schwartz N., Su L., Burkly L. C., Mackay M., Aranow C., Kollaros M., et al. (2006). Urinary TWEAK and the Activity of Lupus Nephritis. J. Autoimmun. 27 (4), 242–250. 10.1016/j.jaut.2006.12.003
    1. Stohl W., Metyas S., Tan S. M., Cheema G. S., Oamar B., Roschke V., et al. (2004). Inverse Association between Circulating APRIL Levels and Serological and Clinical Disease Activity in Patients with Systemic Lupus Erythematosus. Ann. Rheum. Dis. 63 (9), 1096–1103. 10.1136/ard.2003.018663
    1. Stohl W., Metyas S., Tan S. M., Cheema G. S., Oamar B., Xu D., et al. (2003). B Lymphocyte Stimulator Overexpression in Patients with Systemic Lupus Erythematosus: Longitudinal Observations. Arthritis Rheum. 48 (12), 3475–3486. 10.1002/art.11354
    1. van Vollenhoven R. F., Petri M. A., Cervera R., Roth D. A., Ji B. N., Kleoudis C. S., et al. (2012). Belimumab in the Treatment of Systemic Lupus Erythematosus: High Disease Activity Predictors of Response. Ann. Rheum. Dis. 71 (8), 1343–1349. 10.1136/annrheumdis-2011-200937
    1. Vincent F. B., Kandane-Rathnayake R., Koelmeyer R., Hoi A. Y., Harris J., Mackay F., et al. (2019). Analysis of Serum B Cell-Activating Factor from the Tumor Necrosis Factor Family (BAFF) and its Soluble Receptors in Systemic Lupus Erythematosus. Clin. Transl Immunol. 8 (4), e01047. 10.1002/cti2.1047
    1. Ware C. F. (2013). Protein Therapeutics Targeted at the TNF Superfamily. Adv. Pharmacol. 66, 51–80. 10.1016/B978-0-12-404717-4.00002-0
    1. Yazdany J., Davis J. (2004). The Role of CD40 Ligand in Systemic Lupus Erythematosus. Lupus. 13 (5), 377–380. 10.1191/0961203304lu1030oa
    1. Zhao Z., Burkly L. C., Campbell S., Schwartz N., Molano A., Choudhury A., et al. (2007). TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-Versus-Host Model of Systemic Lupus Erythematosus. J. Immunol. 179 (11), 7949–7958. 10.4049/jimmunol.179.11.7949

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe