Abstract
The use of B-cell depleting agents in clinical practice in systemic lupus erythematosus (SLE), overwhelmingly restricted to off-label therapy with rituximab, currently centers on patients unresponsive or intolerant to standard of care therapy, or with life-threatening presentations. Four B-cell depleting agents deserve specific mention: rituximab, use of which is reported in nearly 1,500 patients with SLE (1,000 in uncontrolled studies); ocrelizumab, trials of which were halted in 2010 owing to an association with unexpectedly high rates of severe infections; epratuzumab, which has been tested in trials that enrolled nearly 300 patients with SLE; and belimumab, tested in more than 2,000 patients with SLE overwhelmingly included in controlled trials. Belimumab has been licensed for use in SLE in 2011 by the FDA and European Medicines Agency. Forthcoming years will show the real value of B-cell targeted therapies, including the off-label use of rituximab and especially the licensed use of belimumab, as part of the standard of care in patients with SLE.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bernatsky S, Ramsey-Goldman R, Labrecque J, Joseph L, Boivin JF, Petri M, Zoma A, Manzi S, Urowitz MB, Gladman D, Fortin PR, Ginzler E, Yelin E, Bae SC, Wallace DJ, Edworthy S, Jacobsen S, Gordon C, Dooley MA, Peschken CA, Hanly JG, Alarcón GS, Nived O, Ruiz-Irastorza G, Isenberg D, Rahman A, Witte T, Aranow C, Kamen DL, Steinsson K, Askanase A, Barr S, Criswell LA, Sturfelt G, Patel NM, Senécal JL, Zummer M, Pope JE, Ensworth S, El-Gabalawy H, McCarthy T, Dreyer L, Sibley J, St Pierre Y, Clarke AE (2013a) Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun 42:130–135
Bernatsky S, Ramsey-Goldman R, Joseph L, Boivin JF, Costenbader KH, Urowitz MB, Gladman DD, Fortin PR, Nived O, Petri MA, Jacobsen S, Manzi S, Ginzler EM, Isenberg D, Rahman A, Gordon C, Ruiz-Irastorza G, Yelin E, Bae SC, Wallace DJ, Peschken CA, Dooley MA, Edworthy SM, Aranow C, Kamen DL, Romero-Diaz J, Askanase A, Witte T, Barr SG, Criswell LA, Sturfelt GK, Blanco I, Feldman CH, Dreyer L, Patel NM, St Pierre Y, Clarke AE. (2013b) Lymphoma risk in systemic lupus: effects of disease activity versus treatment. Ann Rheum Dis [Epub ahead of print] PubMed PMID: 23303389
Burness CB, McCormack PL (2011) Belimumab: in systemic lupus erythematosus. Drugs 71:2435–2444
Cancro MP, D’Cruz DP, Khamashta MA (2009) The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest 119:1066–1073
Chiche L, Jourde N, Mancini J (2011) Belimumab for systemic lupus erythematosus. Lancet 377:2080
Coca A, Sanz I (2012) Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumatol 24:451–456
D’Cruz D, Manzi S, Sánchez-Guerrero J, BLISS-52 and BLISS-76 Study Groups (2011) Belimumab reduced disease activity across multiple organ domains in patients with SLE: combined results from BLISS-52 and BLISS-76. Ann Rheum Dis (Abstract THU0421)
Dall’Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, Kalunian K, Dhar P, Vincent E, Pena-Rossi C, Wofsy D (2007) Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 56:4142–4150
Dooley MD, Houssiau F, Aranow C, D’Cruz D, Askanase AD, Roth D, Zhong ZJ, Freimuth W, Ginzler EM, BLISS-52/-76 Study Groups (2011) Effect of belimumab treatment on renal outcomes: results from phase 3 belimumab clinical trials in patients with systemic lupus erythematosus. Arthritis Rheum 63(Suppl):2472(S963)
Engel P, Gómez-Puerta JA, Ramos-Casals M, Lozano F, Bosch X (2011) Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol Rev 63:127–156
European Medicines Agency (EMEA) (2013) Benlysta leaflet. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002015/human_med_001466.jsp&mid=WC0b01ac058001d124&jsenabled=true. Accessed 15 Apr 2013
Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF, BLISS-76 Study Group (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
Genovese MC, Kinnman N, de La Bourdonnaye G, Pena Rossi C, Tak PP (2011) Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum 63:1793–1803
Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, Singer NG (2012) Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther 14:R33
Gregersen JW, Jayne DR (2012) B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 9:505–514
Hahn BH (2013) Belimumab for systemic lupus erythematosus. N Engl J Med 368(16):1528–1535
Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall’Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ (2010) B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther 335:213–222, Erratum in: J Pharmacol Exp Ther 2011, 336, 294
Horowitz DL, Furie R (2012) Belimumab is approved by the FDA: what more do we need to know to optimize decision making? Curr Rheumatol Rep 14:318–323
Jiménez-Alonso J (2012) Clinical guidelines of the Spanish Society of Internal Medicine: Systemic lupus erythematosus, Spanish Study Group of Systemic Autoimmune Diseases (GEAS) http://www.fesemi.org/grupos/autoinmunes/docencia/guias/view#les_2011
Li J, Pan HF, Cen H, Tian J, Ma Y, Tao JH, Ye DQ (2011) Interleukin-21 as a potential therapeutic target for systemic lupus erythematosus. Mol Biol Rep 38:4077–4081
Lied GA, Berstad A (2011) Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review. Scand J Immunol 73:1–7
Manzi S, Gladman D, Navarra S, Sanchez-Guerrero J, D’Cruz D, Freimuth W, Zhong ZJ, Keenan G and BLISS-52 and BLISS-76 Study Groups (2011) Organ domain item analysis of systemic lupus erythematosus patients treated in phase 3 belimumab clinical trials. Arthritis Rheum 63(Suppl):602(S231)
Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, Ginzler EM, D’Cruz DP, Doria A, Cooper S, Zhong ZJ, Hough D, Freimuth W, Petri MA, The BLISS-52 and BLISS-76 Study Groups (2012) Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 71:1833–1838
Mariño E, Grey ST (2012) B cells as effectors and regulators of autoimmunity. Autoimmunity 45:377–387
Mauri C, Bosma A (2012) Immune regulatory function of B cells. Annu Rev Immunol 30:221–241
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62:222–233
Merrill JT, Ginzler EM, Wallace DJ, McKay JD, Lisse JR, Aranow C, Wellborne FR, Burnette M, Condemi J, Zhong ZJ, Pineda L, Klein J, Freimuth WW, LBSL02/99 Study Group (2012) Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum 64:3364–3373
Morel J, Hahne M (2013) To target or not to target APRIL in systemic lupus erythematosus: that is the question! Arthritis Res Ther 15:107
Navarra SV, Guzmán RM, Gallacher AE, BLISS-52 Study Group et al (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377:721–731
Pena-Rossi C, Nasonov E, Stanislav M, Yakusevich V, Ershova O, Lomareva N, Saunders H, Hill J, Nestorov I (2009) An exploratory dose-escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus. Lupus 18:547–555
Petri M, Hu W, Fang H, Xu J, Bienkowska J, Allaire N, Carulli J, Linnik MD (2011) Association between B-Cell activating factor gene expression and disease characteristics in systemic lupus erythematosus. Arthritis Rheum 63(Suppl):585(S223)
Ramos-Casals M, Khamashta MA (2012) Connective tissue disease: trial of SLE therapies in real-world settings. Nat Rev Rheumatol 8:128–130
Ramos-Casals M, Díaz-Lagares C, Khamashta MA (2009a) Rituximab and lupus: good in real life, bad in controlled trials. Comment on the article by Lu et al. Arthritis Rheum 61:1281–1282
Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA (2009b) Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus 18:767–776
Ramos-Casals M, Díaz-Lagares C, Khamashta MA, Grupo de Trabajo de Enfermedades Autoinmunes Sistémicas de la Sociedad Española de Medicina Interna (2011a) B-cell-depletion therapy in systemic autoimmune diseases. Recommendations for use in clinical practice. Med Clin (Barc) 12:257–263
Ramos-Casals M, Diaz-Lagares C, Soto-Cardenas MJ, Brito-Zeron P, Cuadrado MJ, Sanna G, Bertolaccini L, Khamashta MA (2011b) Rituximab therapy in lupus nephritis: current clinical evidence. Clin Rev Allergy Immunol 40:159–169
Ramos-Casals M, Sanz I, Bosch X, Stone JH, Khamashta MA (2012) B-cell-depleting therapy in systemic lupus erythematosus. Am J Med 125:327–336
Ramos-Casals M, Ruiz-Irastorza G, Jiménez-Alonso J, Khamashta MA, Grupo de Trabajo de Enfermedades Autoinmunes Sistémicas (GEAS) de la Sociedad Española de Medicina Interna (SEMI) (2013) Belimumab in systemic lupus erythematosus: a guide for its use in the daily practice. Rev Clin Esp 213:66–67
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G, LUNAR Investigator Group (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum 64:1215–1226
Ruiz-Irastorza G, Danza A, Khamashta M (2012) Glucocorticoid use and abuse in SLE. Rheumatology (Oxford) 51:1145–1153
Sanz I, Yasothan U, Kirkpatrick P (2011) Belimumab. Nat Rev Drug Discov 10:335–336
Scott LJ, Burness CB, McCormack PL (2012) Belimumab: a guide to its use in systemic lupus erythematosus. BioDrugs 26:195–199
Stohl W, Hilbert DM (2012) The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol 30:69–77
Strand V, Cooper S, Zhong ZJ, Dennis G (2011) Responders in the phase 3 belimumab clinical trials in patients with systemic lupus erythematosus reported improvements in fatigue and health-related quality of life at week 52. Arthritis Rheum 63 (Suppl):1369(S535)
Treamtrakanpon W, Tantivitayakul P, Benjachat T, Somparn P, Kittikowit W, Eiam-Ong S, Leelahavanichkul A, Hirankarn N, Avihingsanon Y (2012) APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis. Arthritis Res Ther 14:R252
van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J (2011a) Atacicept in patients with rheumatoid arthritis and inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum 63:1782–1792
van Vollenhoven RF, Schwarting A, Navarra S, et al (2011b) Durability of response in SLE patients treated with belimumab in the phase 3 BLISS-52 and BLISS-76 studies. Ann Rheum Dis (Abstract THU0431)
van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, Zhong ZJ, Freimuth W (2012) Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 71:1343–1349
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Basel
About this chapter
Cite this chapter
Brito-Zerón, P., Soto-Cárdenas, M.J., Retamozo, S., Bosch, X., Ramos-Casals, M., Khamashta, M.A. (2014). Systemic Lupus Erythematosus: Indirect B-Cell Blocking. In: Bosch, X., Ramos-Casals, M., Khamashta, M. (eds) Drugs Targeting B-Cells in Autoimmune Diseases. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0706-7_5
Download citation
DOI: https://doi.org/10.1007/978-3-0348-0706-7_5
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0348-0705-0
Online ISBN: 978-3-0348-0706-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)