rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2013-1494rsp-1310Research ArticleСтатьиArticlesРитуксимаб в терапии системной красной волчанкиRituximab in the management of systemic lupus erythematosusLevitskyAdrianLevitskyAdrian

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

-LinderSaraLinderSara

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

-RonaldF. VollenhovenRonaldF. Vollenhoven

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID)

-201315062013513№3 (2013)223239Copyright © Levitsky A., Linder S., Ronald F.V., 20132013Levitsky A., Linder S., Ronald F.V.Levitsky A., Linder S., Ronald F.V.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/1310

Цель работы — обзор данных об эффективности ритуксимаба (РТМ) — генно-инженерного биологического препарата, представляющего собой моноклональное антитело к CD20, при лечении системной красной волчанки (СКВ) с вовлечением и без вовлечения почек в неконтролируемых и контролируемых исследованиях. Неконтролируемые исследования продемонстрировали возможность применения РТМ как средства лечения СКВ, однако в двух контролируемых испытаниях, посвященных терапии СКВ с вовлечением и без вовлечения почек, его эффективность не подтвердилась. Есть причины считать, что эти контролируемые испытания не были спланированы должным образом, и сейчас готовится проведение дополнительных контролируемых исследований для получения более обширных данных по этому вопросу. В настоящей работе мы обсуждаем результаты как контролируемых, так и неконтролируемых наблюдений, в которых оценивался РТМ. Мы также приводим возможные причины различий в полученных результатах и предлагаем планы дальнейших исследований — дозы препаратов, сопутствующие лекарственные средства, продолжительность наблюдений. Наконец, мы сообщаем о трех планируемых контролируемых испытаниях, в которых будут предприняты попытки решить эти важные вопросы.

Objective: To review the effects of the biologic monoclonal anti-CD-20 antibody, rituximab, on renal and non-renal systemic lupus erythematosus in both uncontrolled and controlled studies. Summary: Uncontrolled studies have demonstrated potential for rituximab in treating lupus patients, but two controlled trials, one each in renal and non-renal lupus, did not confirm this. There remain reasons to believe that these controlled trials may have not been designed optimally and additional controlled trials are currently being planned to provide more data on this issue. In this review, we introduce rituximab and investigate both controlled and uncontrolled observations involving this drug. We also discuss possible reasons for the differences between their findings and provide suggestions for potential avenues of investigation, i.e. treatment dosages, concomitant treatment, and study length. Finally, we introduce three upcoming controlled trials that seek to address these important unsolved questions.

References<div><p>Wallace D.J. Management of Nonrenal Systemic Lupus erythematosus. In: M.H. Weisman, M.E. Weinblatt, J.S. Louie, R.F. van Vollenhoven (eds). Targeted Treatment of the Rheumatic Diseases. 1st ed. Philadelphia, PA: Saunders Elsevier, 2010;9:91-105</p><p>Ishimori M., Weisman M.H., Setooden K., Wallace D.J. Principles of Therapy, Local Measures, and Nonsteroidal Medications. In: D.J. Wallace, Hannahs Hahn (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;47:582-90</p><p>Touma Z., Gladman D.G., Urowits M.B. Clinical Measures, Metrics, and Indices. In: D.J. Wallace, Hannahs Hahn (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;46:563-9.</p><p>Navarra S.V., Naidas O.D. Management of Systemic Lupus Erythematosus Renal Disease. In: M.H. Weisman, M.E.Weinblatt, J.S. Louie, R.F. van Vollenhoven (eds). Targeted Treatment of the Rheumatic Diseases. 1th ed. Philadelphia, PA: Saunders Elsevier, 2010;10:108-20.</p><p>Carrido J. Diffuse and Focal Proliferative Lupus Nephritis Treatment Review. The Role of Mycophenolate mofetil. CIN 2011 6th Congress of Nephrology in Internet. 2011; http://traba-hos.cin2011.uninet.edu/132/garrido.pdf</p><p>Appel G.B., Contreras G., Dooley M.A. et al. Mycophenolate mofetil versus cyclophoaphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103-12.</p><p>Pepper R., Griffith M., Kirwan C. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant 2009;1-7.</p><p>Chan T.M., Li F.K., Tang C.S.O. et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156-62.</p><p>Dooley M.A., Jayne D., Ginzler E.M. et al. Mycophenolate versus azathioprine (as maintenance therapy of lupus nephritis). N Engl J Med 2011;365:1886-95.</p><p>Houssiau F.A., Cruz D.D., Sangle S. et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from MAINTAIN Nephritis trial. Ann Rheum Dis 2010;69:2083-9.</p><p>Van Vollenhoven R.F. Novel Therapies for SLE: Biological Agents Available in PracticeToday. In: D.J. Wallace, Hannahs Hahn B. (eds). Dubois’ Lupus Erythematosis and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;53:642-5.</p><p>Van Vollenhoven R.F. Rituximab Shadow, illusion or light? Autoim Rev 2012;11:563-7.</p><p>Badin F., Hayslip J. Rituximab in the treatment of B-cell non-Hodgkin lymphoma, focus on outcomes and comparative effectiveness. Clin Econom Out Res 2010;2:37-45.</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 a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthr Rheum 2006;54:2793-806.</p><p>Jayne D. Rituximab Treatment for Vasculitis. J Am Soc Nephrol 2010;5:1359-62.</p><p>Gorman C., Leandro M., Isenberg D. Does B-cell depletion have a role to play in the treatment of systemic lupus erythematosus? Lupus 2004;13:312-6.</p><p>Ramos-Casals M., Soto M.J., Cuadrado M.J., Khamashta M.A. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18:767-76.</p><p>DrugBank (1997). Open Data Drug &amp; Drug Target Database. FDA Label: RITUXAN, Rituximab. IDEC Pharmaceuticals Corporation and Genentech, Inc. Retrieved December 20th, 2012, from: http://www.drugbank.ca/system/fda labels/DB00073.pdf?1265922801</p><p>Smith M.R. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003;22:7359-68.</p><p>Rovin B.H., Furie R., Latinis K. et al. Efficacy and safety of rituximab in with Rituximab study. Arthr Rheum 2012;64:1215-36.</p><p>Jonsdottir T., Gunnarsson I., Lisselada A. et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis 2008;67:330-4.</p><p>Leandro M.J., Edwards J.C.W., Cambridge G., Ehrenstein M.R. B-cell repopulation occurs mainly from naive B-cells in patients with rheumatoid arthritis and systemic lupus erythematosus treated with rituximab. Arthr Rheum 2003;48(Suppl):464.</p><p>Gunnarsson I., Sundelin B., Jonsdottir T. et al. Histopathologic and clinical proliferative lupus nephritis. Arthr Rheum 2007;56:1263-72.</p><p>Jonsdottir T., Zickert A., Sundelin B. et al. Long-term follow-up in lupus nephritis patients treated with rituximab clinical and histopathological response. Rheumatology (Oxford) 2013 [Epub ahead of print]; PubMed PMID: 23287364.</p><p>Merrill J.T., Neuwelt C.M., Wallace D.J. et al. Efficacy and safety of rituximab in moderate-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthr Rheum 2010;62:222-33.</p><p>Li E.K., Tam L.S., Zhu T.Y. et al. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rheumatology 2009;48:892-8.</p><p>Hahn B. The Pathogenesis of SLE. In: D.J. Wallace, Hannah Hahn B. (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;3:29-32.</p></div><br /><div><p>Wallace D.J. Management of Nonrenal Systemic Lupus erythematosus. In: M.H. Weisman, M.E. Weinblatt, J.S. Louie, R.F. van Vollenhoven (eds). Targeted Treatment of the Rheumatic Diseases. 1st ed. Philadelphia, PA: Saunders Elsevier, 2010;9:91-105</p><p>Ishimori M., Weisman M.H., Setooden K., Wallace D.J. Principles of Therapy, Local Measures, and Nonsteroidal Medications. In: D.J. Wallace, Hannahs Hahn (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;47:582-90</p><p>Touma Z., Gladman D.G., Urowits M.B. Clinical Measures, Metrics, and Indices. In: D.J. Wallace, Hannahs Hahn (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;46:563-9.</p><p>Navarra S.V., Naidas O.D. Management of Systemic Lupus Erythematosus Renal Disease. In: M.H. Weisman, M.E.Weinblatt, J.S. Louie, R.F. van Vollenhoven (eds). Targeted Treatment of the Rheumatic Diseases. 1th ed. Philadelphia, PA: Saunders Elsevier, 2010;10:108-20.</p><p>Carrido J. Diffuse and Focal Proliferative Lupus Nephritis Treatment Review. The Role of Mycophenolate mofetil. CIN 2011 6th Congress of Nephrology in Internet. 2011; http://traba-hos.cin2011.uninet.edu/132/garrido.pdf</p><p>Appel G.B., Contreras G., Dooley M.A. et al. Mycophenolate mofetil versus cyclophoaphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103-12.</p><p>Pepper R., Griffith M., Kirwan C. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant 2009;1-7.</p><p>Chan T.M., Li F.K., Tang C.S.O. et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156-62.</p><p>Dooley M.A., Jayne D., Ginzler E.M. et al. Mycophenolate versus azathioprine (as maintenance therapy of lupus nephritis). N Engl J Med 2011;365:1886-95.</p><p>Houssiau F.A., Cruz D.D., Sangle S. et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from MAINTAIN Nephritis trial. Ann Rheum Dis 2010;69:2083-9.</p><p>Van Vollenhoven R.F. Novel Therapies for SLE: Biological Agents Available in PracticeToday. In: D.J. Wallace, Hannahs Hahn B. (eds). Dubois’ Lupus Erythematosis and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;53:642-5.</p><p>Van Vollenhoven R.F. Rituximab Shadow, illusion or light? Autoim Rev 2012;11:563-7.</p><p>Badin F., Hayslip J. Rituximab in the treatment of B-cell non-Hodgkin lymphoma, focus on outcomes and comparative effectiveness. Clin Econom Out Res 2010;2:37-45.</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 a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthr Rheum 2006;54:2793-806.</p><p>Jayne D. Rituximab Treatment for Vasculitis. J Am Soc Nephrol 2010;5:1359-62.</p><p>Gorman C., Leandro M., Isenberg D. Does B-cell depletion have a role to play in the treatment of systemic lupus erythematosus? Lupus 2004;13:312-6.</p><p>Ramos-Casals M., Soto M.J., Cuadrado M.J., Khamashta M.A. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18:767-76.</p><p>DrugBank (1997). Open Data Drug &amp; Drug Target Database. FDA Label: RITUXAN, Rituximab. IDEC Pharmaceuticals Corporation and Genentech, Inc. Retrieved December 20th, 2012, from: http://www.drugbank.ca/system/fda labels/DB00073.pdf?1265922801</p><p>Smith M.R. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003;22:7359-68.</p><p>Rovin B.H., Furie R., Latinis K. et al. Efficacy and safety of rituximab in with Rituximab study. Arthr Rheum 2012;64:1215-36.</p><p>Jonsdottir T., Gunnarsson I., Lisselada A. et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis 2008;67:330-4.</p><p>Leandro M.J., Edwards J.C.W., Cambridge G., Ehrenstein M.R. B-cell repopulation occurs mainly from naive B-cells in patients with rheumatoid arthritis and systemic lupus erythematosus treated with rituximab. Arthr Rheum 2003;48(Suppl):464.</p><p>Gunnarsson I., Sundelin B., Jonsdottir T. et al. Histopathologic and clinical proliferative lupus nephritis. Arthr Rheum 2007;56:1263-72.</p><p>Jonsdottir T., Zickert A., Sundelin B. et al. Long-term follow-up in lupus nephritis patients treated with rituximab clinical and histopathological response. Rheumatology (Oxford) 2013 [Epub ahead of print]; PubMed PMID: 23287364.</p><p>Merrill J.T., Neuwelt C.M., Wallace D.J. et al. Efficacy and safety of rituximab in moderate-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthr Rheum 2010;62:222-33.</p><p>Li E.K., Tam L.S., Zhu T.Y. et al. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rheumatology 2009;48:892-8.</p><p>Hahn B. The Pathogenesis of SLE. In: D.J. Wallace, Hannah Hahn B. (eds). Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Saunders Elsevier, 2012;3:29-32.</p></div><br />

The authors declare that there are no conflicts of interest present.