rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2013-1256rsp-1157Research ArticleСтатьиArticlesГомеостаз В-лимфоцитов и направления анти-В-клеточной терапии при ревматоидном артритеB-lymphocyte hemostasis and anti-B-cell therapy areas for rheumatoid arthritisSuponitskayaEkaterina ValeryevnaSuponitskayaEkaterina Valeryevnaekaterina.s@mtu-net.ruАлександроваЕлена НиколаевнаAleksandrovaE N-AleksankinA PAleksankinA P-НасоновЕвгений ЛьвовичNasonovE L-201304112013514№4 (2013)432438Copyright © Suponitskaya E.V., Александрова Е.Н., Aleksankin A.P., Насонов Е.Л., 20132013Suponitskaya E.V., Александрова Е.Н., Aleksankin A.P., Насонов Е.Л.Suponitskaya E.V., Aleksandrova E.N., Aleksankin A.P., Nasonov E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/1157References<div><p>Насонов Е.Л., Каратеев Д.Е., Балабанова Р.М. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. Под ред. Е.Л. Насонова, В.А. Насоновой. М.:ГЭОТАР-Медиа, 2008; 290-331.</p><p>Klareskog L., Catrina A.I., Paget S. Rheumatoid arthritis. Lancet 2009;373:659-72.</p><p>Scott D.L., Wolfe F., Huizinga T.W. Rheumatoid arthritis. Lancet 2010;376:1094-108.</p><p>Carson D.A., Chen P.P., Kipps T.J. New roles for rheumatoid factor. J Clin Invest 1991;87:379-83.</p><p>Edwards J.C., Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 2001;40:205-11.</p><p>Kim H.J., Berek C. B cells in rheumatoid arthritis. Arthr Res 2000;2:126-31.</p><p>Metlay J.P., Pure E., Steinman R.M. Control of the immune response at the level of antigen-presenting cells: a comparison of the function of dendritic cells and B lymphocytes. Adv Immunol 1989;47:45-116.</p><p>Takemura S., Klimiuk P.A., Braun A. et al. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.</p><p>Dörner T., Lipsky P.E. B-cell targeting: a novel approach to immune intervention today and tomorrow. Expert Opin Biol Ther 2007;7:1287-99.</p><p>Dö rner T., Jacobi A.M., Lipsky P.E. B cells in autoimmunity. Arthr Res Ther 2009;11:247.</p><p>Sims G.P., Ettinger R., Shirota Y. et al. Identification and characterization of circulating human transitional B cells. Blood 2005;105:4390-8.</p><p>Anolik J.H., Looney R.J., Lund F.E. et al. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res 2009;45:144-58.</p><p>Sanz I., Wei C., Lee F.E., Anolik J. Phenotypic and functional heterogeneity of human memory B cells. Semin Immunol 2008;20:67-82.</p><p>Jacobi A.M., Reiter K., Mackay M. et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthr Rheum 2008;58:1762-73.</p><p>Насонов Е.Л. Применение ритуксимаба при ревматоидном артрите. Науч-практич ревматол 2009;1(Прил.):3—22.</p><p>Samuels J., Ng Y.S., Coupillaud C. et al. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med 2005;201:1659-67.</p><p>Takemura S., Klimiuk P.A., Braun A. et al. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.</p><p>Mauri C., Ehrenstein M.R. Cells of the synovium in rheumatoid arthritis. B cells. Arthr Res Ther 2007;9:205.</p><p>Kuhn K.A., Kulik L., Tomooka B. et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 2006;116:961-73.</p><p>Lindenau S., Scholze S., Odendahl M. et al. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann NY Acad Sci 2003;987:246-8.</p><p>Henneken M., Dö rner T., Burmester G.R., Berek C. Differential expression of chemokine receptors on peripheral blood B cells from patients with rheumatoid arthritis and systemic lupus erythematosus. Arthr Res Ther 2005;7:R1001-R1013.</p><p>Kessel A., Snir A., Toubi E. The role of B cells in immunoregulation. In: Conrad K., Chan E.K.L., Fritzler M.J. et al. From pathogenesis to therapy of autoimmune diseases. Report on the 9th Dresden symposium on autoantibodies held in Dresden on September 2-5, 2009. Autoantigens, autoantibodies, autoimmuni-ty.Vol.6.2009. Lengerich-Berlin-Bremen-Miami-Riga-Viernheim-Wien-Zagreb: Past Science Publishers, 2009;523-30.</p><p>Wolf S.D., Dittel B.N., Hardardottir F., Janeway C.A.Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 1996;184:2271-8.</p><p>Mizoguchi A., Bhan A.K. A case for regulatory B cells. J Immunol 2006;176:705-10.</p><p>Jamin C., Morva A., Lemoine S. et al. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthr Rheum 2008;58:1900-6.</p><p>Amu S., Tarkowski A., Dörner T. et al. The human immunomodulatory CD25+ B cell population belongs to the memory B cell pool. Scand J Immunol 2007;66:77-86.</p><p>Taylor P.C., Quattrocchi E., Mallett St. et al. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis 2011;70:2119-25.</p><p>Rigby W., Tony H.P., Oelke K. et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthr Rheum 2012;64:350-9.</p><p>Van Vollenhoven R.F., Kinnman N., Vincent E. et al. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthr Rheum 2011;63:1782-92.</p><p>Einfeld D.A., Brown J.P., Valentine M.A. et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988;7:711-7.</p><p>Valentine M.A., Meier K.E., Rossie S. et al. Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. Regulation by protein kinase C. J Biol Chem 1989;264:11282-7.</p><p>Stashenko P., Nadler L.M., Hardy R. et al. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980;125:1678-85.</p><p>Tedder T.F., Boyd A.W., Freedman A.S. et al. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 1985;135:973-9.</p><p>Leget G.A., Czuczman M.S. Use of rituximab, the new FDA-approved antibody. Curr Opin Oncol 1998;10:548-51.</p><p>Edwards J.C., Szczepanski L., Szechinski J. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81.</p><p>Emery P., Fleischmann R., Filipowicz-Sosnowska A. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthr Rheum 2006;54:1390-400.</p><p>Cohen S.B., Emery P., Greenwald M.W. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Results of multicenter, randomized, double-blind, placebocontrolled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthr Rheum 2006;54:2793-806.</p><p>Leandro M.J., Cambridge G., Ehrenstein M.R., Edwards J.C.W. Reconstitution of peripheral blood B cell after depletion with rit-uximab in patients with rheumatoid arthritis. Arthr Rheum 2006;54:613-20.</p><p>Roll P., Palanichamy A., Kneitz C. et al. Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthr Rheum 2006;54:2377-86.</p><p>Roll P., Dorner T., Tony H.-P. Anti-CD20 therapy in patients with rheumatoid arthritis: predictors of response and B cell subset regeneration after repeated treatment. Arthr Rheum 2008;58:1566-75.</p><p>Looney R.J. Update on the use of rituximab for intractable rheumatoid arthritis. Open Access Rheumatol Res Rev 2009;1:83-94.</p><p>De Vita S., Zaja F., Sacco S. et al. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthr Rheum 2002;46:2029-33.</p><p>Leandro M.J., Edwards J.C., Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 2002;61:883-8.</p><p>Breedveld F., Agarwal S., Yin M. et al. Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response. J Clin Pharmacol 2007;47:1119-28.</p><p>Dass S., Rawstron A.C., Vital E.M. et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthr Rheum 2008;58:2993-9.</p><p>Vital E.M., Dass S., Rawstron A.C. et al. Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. Arthr Rheum 2010;62:1273-9.</p><p>Vital E.M., Rawstron A.C., Dass S. et al. Reduced-dose rituximab in rheumatoid arthritis: efficacy depends on degree of B cell depletion. Arthr Rheum 2011;63:603-8.</p><p>Sellam J., Rouanet S., Hendel-Chavez H. et al. Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis. Arthr Rheum 2011;63:3692-701.</p><p>Brezinschek H.-P., Rainer F., Brickmann K., Graninger W.B. B lymphocyte-typing for prediction of clinical response to rituximab. Arthr Res Ther 2012;14:R161.</p><p>Möller B., Aeberli D., Eggli S. et al. Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis. Arthr Res Ther 2009;11:R62.</p><p>Teng Y.K., Levarht E.W., Toes R.E. et al. Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation. Ann Rheum Dis 2009;68:1011-6.</p><p>Nakou M., Katsikas G., Sidiropoulos P. et al. Rituximab therapy reduced activated B cell in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cell correlates with clinical response. Arthr Res Therapy 2009;11:R131.</p><p>Rehnberg M., Amu S., Tarkowski A. et al. Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis. Arthr Res Ther 2009;11:R123.</p><p>Vancsa A., Szabo Z., Szamosi S. et al. Longterm effects of rituximab on B cell counts and autoantibody production in rheumatoid arthritis: use of high-sensitivity flow cytometry for more sensitive assessment of B cell depletion. J Rheumatol 2013;40:565-71.</p><p>Fonseca J.E., Santos M.J., Canhao H., Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 2009;8:538-42.</p><p>Madhok R., Crilly A., Watson J., Capell H.A. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52:232-4.</p><p>Houssiau F.A., Devogelaer J.P., van Damme J. et al. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthr Rheum 1988;31:784-8.</p><p>Kotake S., Sato K., Kim K.J. et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996;11:88-95.</p><p>Dayer J.M., Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford) 2010;49:15-24.</p><p>Ballara S., Taylor P.C., Reusch P. et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthr Rheum 2001;44:2055-64.</p><p>Emery P., Keystone E., Tony H.P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebocontrolled trial [published erratum appears in Ann Rheum Dis 2009;68:296]. Ann Rheum Dis 2008;67:1516-23.</p><p>Roll P., Muhammad K., Schumann M. et al. In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment. Arthr Rheum 2011;63:1255-64.</p><p>Mahmood Z., Muhammad Kh., Roll P. et al. IL-6 receptor inhibition by Tocilizumab modulates double negative (CD19IgD-CD27) B Cells in RA [abstract]. Arthr Rheum 2012;64(Suppl 10):1762.</p></div><br /><div><p>Насонов Е.Л., Каратеев Д.Е., Балабанова Р.М. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. Под ред. Е.Л. Насонова, В.А. Насоновой. М.:ГЭОТАР-Медиа, 2008; 290-331.</p><p>Klareskog L., Catrina A.I., Paget S. Rheumatoid arthritis. Lancet 2009;373:659-72.</p><p>Scott D.L., Wolfe F., Huizinga T.W. Rheumatoid arthritis. Lancet 2010;376:1094-108.</p><p>Carson D.A., Chen P.P., Kipps T.J. New roles for rheumatoid factor. J Clin Invest 1991;87:379-83.</p><p>Edwards J.C., Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 2001;40:205-11.</p><p>Kim H.J., Berek C. B cells in rheumatoid arthritis. Arthr Res 2000;2:126-31.</p><p>Metlay J.P., Pure E., Steinman R.M. Control of the immune response at the level of antigen-presenting cells: a comparison of the function of dendritic cells and B lymphocytes. Adv Immunol 1989;47:45-116.</p><p>Takemura S., Klimiuk P.A., Braun A. et al. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.</p><p>Dörner T., Lipsky P.E. B-cell targeting: a novel approach to immune intervention today and tomorrow. Expert Opin Biol Ther 2007;7:1287-99.</p><p>Dö rner T., Jacobi A.M., Lipsky P.E. B cells in autoimmunity. Arthr Res Ther 2009;11:247.</p><p>Sims G.P., Ettinger R., Shirota Y. et al. Identification and characterization of circulating human transitional B cells. Blood 2005;105:4390-8.</p><p>Anolik J.H., Looney R.J., Lund F.E. et al. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res 2009;45:144-58.</p><p>Sanz I., Wei C., Lee F.E., Anolik J. Phenotypic and functional heterogeneity of human memory B cells. Semin Immunol 2008;20:67-82.</p><p>Jacobi A.M., Reiter K., Mackay M. et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthr Rheum 2008;58:1762-73.</p><p>Насонов Е.Л. Применение ритуксимаба при ревматоидном артрите. Науч-практич ревматол 2009;1(Прил.):3—22.</p><p>Samuels J., Ng Y.S., Coupillaud C. et al. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med 2005;201:1659-67.</p><p>Takemura S., Klimiuk P.A., Braun A. et al. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.</p><p>Mauri C., Ehrenstein M.R. Cells of the synovium in rheumatoid arthritis. B cells. Arthr Res Ther 2007;9:205.</p><p>Kuhn K.A., Kulik L., Tomooka B. et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 2006;116:961-73.</p><p>Lindenau S., Scholze S., Odendahl M. et al. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann NY Acad Sci 2003;987:246-8.</p><p>Henneken M., Dö rner T., Burmester G.R., Berek C. Differential expression of chemokine receptors on peripheral blood B cells from patients with rheumatoid arthritis and systemic lupus erythematosus. Arthr Res Ther 2005;7:R1001-R1013.</p><p>Kessel A., Snir A., Toubi E. The role of B cells in immunoregulation. In: Conrad K., Chan E.K.L., Fritzler M.J. et al. From pathogenesis to therapy of autoimmune diseases. Report on the 9th Dresden symposium on autoantibodies held in Dresden on September 2-5, 2009. Autoantigens, autoantibodies, autoimmuni-ty.Vol.6.2009. Lengerich-Berlin-Bremen-Miami-Riga-Viernheim-Wien-Zagreb: Past Science Publishers, 2009;523-30.</p><p>Wolf S.D., Dittel B.N., Hardardottir F., Janeway C.A.Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 1996;184:2271-8.</p><p>Mizoguchi A., Bhan A.K. A case for regulatory B cells. J Immunol 2006;176:705-10.</p><p>Jamin C., Morva A., Lemoine S. et al. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthr Rheum 2008;58:1900-6.</p><p>Amu S., Tarkowski A., Dörner T. et al. The human immunomodulatory CD25+ B cell population belongs to the memory B cell pool. Scand J Immunol 2007;66:77-86.</p><p>Taylor P.C., Quattrocchi E., Mallett St. et al. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis 2011;70:2119-25.</p><p>Rigby W., Tony H.P., Oelke K. et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthr Rheum 2012;64:350-9.</p><p>Van Vollenhoven R.F., Kinnman N., Vincent E. et al. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthr Rheum 2011;63:1782-92.</p><p>Einfeld D.A., Brown J.P., Valentine M.A. et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988;7:711-7.</p><p>Valentine M.A., Meier K.E., Rossie S. et al. Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. Regulation by protein kinase C. J Biol Chem 1989;264:11282-7.</p><p>Stashenko P., Nadler L.M., Hardy R. et al. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980;125:1678-85.</p><p>Tedder T.F., Boyd A.W., Freedman A.S. et al. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 1985;135:973-9.</p><p>Leget G.A., Czuczman M.S. Use of rituximab, the new FDA-approved antibody. Curr Opin Oncol 1998;10:548-51.</p><p>Edwards J.C., Szczepanski L., Szechinski J. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81.</p><p>Emery P., Fleischmann R., Filipowicz-Sosnowska A. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthr Rheum 2006;54:1390-400.</p><p>Cohen S.B., Emery P., Greenwald M.W. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Results of multicenter, randomized, double-blind, placebocontrolled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthr Rheum 2006;54:2793-806.</p><p>Leandro M.J., Cambridge G., Ehrenstein M.R., Edwards J.C.W. Reconstitution of peripheral blood B cell after depletion with rit-uximab in patients with rheumatoid arthritis. Arthr Rheum 2006;54:613-20.</p><p>Roll P., Palanichamy A., Kneitz C. et al. Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthr Rheum 2006;54:2377-86.</p><p>Roll P., Dorner T., Tony H.-P. Anti-CD20 therapy in patients with rheumatoid arthritis: predictors of response and B cell subset regeneration after repeated treatment. Arthr Rheum 2008;58:1566-75.</p><p>Looney R.J. Update on the use of rituximab for intractable rheumatoid arthritis. Open Access Rheumatol Res Rev 2009;1:83-94.</p><p>De Vita S., Zaja F., Sacco S. et al. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthr Rheum 2002;46:2029-33.</p><p>Leandro M.J., Edwards J.C., Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 2002;61:883-8.</p><p>Breedveld F., Agarwal S., Yin M. et al. Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response. J Clin Pharmacol 2007;47:1119-28.</p><p>Dass S., Rawstron A.C., Vital E.M. et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthr Rheum 2008;58:2993-9.</p><p>Vital E.M., Dass S., Rawstron A.C. et al. Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. Arthr Rheum 2010;62:1273-9.</p><p>Vital E.M., Rawstron A.C., Dass S. et al. Reduced-dose rituximab in rheumatoid arthritis: efficacy depends on degree of B cell depletion. Arthr Rheum 2011;63:603-8.</p><p>Sellam J., Rouanet S., Hendel-Chavez H. et al. Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis. Arthr Rheum 2011;63:3692-701.</p><p>Brezinschek H.-P., Rainer F., Brickmann K., Graninger W.B. B lymphocyte-typing for prediction of clinical response to rituximab. Arthr Res Ther 2012;14:R161.</p><p>Möller B., Aeberli D., Eggli S. et al. Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis. Arthr Res Ther 2009;11:R62.</p><p>Teng Y.K., Levarht E.W., Toes R.E. et al. Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation. Ann Rheum Dis 2009;68:1011-6.</p><p>Nakou M., Katsikas G., Sidiropoulos P. et al. Rituximab therapy reduced activated B cell in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cell correlates with clinical response. Arthr Res Therapy 2009;11:R131.</p><p>Rehnberg M., Amu S., Tarkowski A. et al. Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis. Arthr Res Ther 2009;11:R123.</p><p>Vancsa A., Szabo Z., Szamosi S. et al. Longterm effects of rituximab on B cell counts and autoantibody production in rheumatoid arthritis: use of high-sensitivity flow cytometry for more sensitive assessment of B cell depletion. J Rheumatol 2013;40:565-71.</p><p>Fonseca J.E., Santos M.J., Canhao H., Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 2009;8:538-42.</p><p>Madhok R., Crilly A., Watson J., Capell H.A. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52:232-4.</p><p>Houssiau F.A., Devogelaer J.P., van Damme J. et al. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthr Rheum 1988;31:784-8.</p><p>Kotake S., Sato K., Kim K.J. et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996;11:88-95.</p><p>Dayer J.M., Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford) 2010;49:15-24.</p><p>Ballara S., Taylor P.C., Reusch P. et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthr Rheum 2001;44:2055-64.</p><p>Emery P., Keystone E., Tony H.P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebocontrolled trial [published erratum appears in Ann Rheum Dis 2009;68:296]. Ann Rheum Dis 2008;67:1516-23.</p><p>Roll P., Muhammad K., Schumann M. et al. In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment. Arthr Rheum 2011;63:1255-64.</p><p>Mahmood Z., Muhammad Kh., Roll P. et al. IL-6 receptor inhibition by Tocilizumab modulates double negative (CD19IgD-CD27) B Cells in RA [abstract]. Arthr Rheum 2012;64(Suppl 10):1762.</p></div><br />
The authors declare that there are no conflicts of interest present.