Cyclophosphamide Versus Rituximab in Progressive Forms of Multiple Sclerosis
-
Masoud Etemadifar
,
Shadi Ghourchian
,
Nazanin Mahinparvar
,
Mehri Salari
,
Fatemeh Etemadifar
,
Yalda Nikanpour
,
Shahin Sanaei
,
Mojtaba Akbari
Abstract
This study aimed to compare the efficacy of rituximab versus Cyclophosphamide on active secondary progressive multiple sclerosis (SPMS). The randomized clinical trial was performed from 2015 to 2017 in multiple sclerosis (MS) clinics affiliated to Isfahan MS society (IMSS). Patients were randomized to two groups, and one of them received Rituximab that was repeated every six months in case of medical indication. The other one received a monthly pulse of methylprednisolone plus cyclophosphamide (Endoxan, Baxter, UK) until two years. Expanded disabilities status scale (EDSS), clinical, and MRI findings were assessed every six months. Statistical analysis was performed using SPSS software. 39 patients in the Rituximab group and 30 in the Cyclophosphamide group with similar age and gender distribution were entered for analysis. At baseline, the mean number of attacks in the Rituximab group was significantly more than the Cyclophosphamide group (P=0.0001). After 6, 12, and 18 months of treatment, the rate of attacks was similar between groups although it increased significantly in the Rituximab group (P=0.030) after 24 months of treatment. EDSS was increased in the Rituximab group more than the other group at the end of the study. Both drugs were well-tolerated by patients. The EDSS was increased in the Rituximab group but the disability score did not worsen in the Cyclophosphamide group. Both therapies were associated with a reduction in disease attacks and improvement in radiologic findings in a two-year period of follow-up.
1. Bishop M, Rumrill PD. Multiple sclerosis: Etiology, symptoms, incidence and prevalence, and implications for community living and employment. Work. 2015;52(4):725-34
2. Dumitrescu L, Constantinescu CS, Tanasescu RSiponimod for the treatment of secondary progressive multiple sclerosis. Expert Opin Pharmacother. 2018 Dec 5:1-8.
3. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1-5.
4. Sellebjerg F, Börnsen L, Ammitzbøll C, Nielsen JE, Vinther-Jensen T, Hjermind LE, von Essen M, Ratzer RL, Soelberg Sørensen P, Romme Christensen J. Defining active progressive multiple sclerosis. Mult Scler. 2017 Nov;23(13):1727-1735
5. Greenfield AL, Hauser SL. B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. 2018 Jan;83(1):13-26.
6. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. New England Journal of Medicine. 2017;376(3):221-34.
7. Lazibat I, Rubinić Majdak M, Županić S. Multiple Sclerosis: New Aspects of Immunopathogenesis. Acta Clin Croat. 2018 Jun;57(2):352-361.
8. Salzer J, Svenningsson R, Alping P, Novakova L, Björck A, Fink K, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. Neurology. 2016:10.1212/WNL
9. Lovett-Racke A, Liu Y, Racke M, Shubin R, Wray S, Su W, et al. Preliminary results of phase 2 multicenter study of ublituximab (UTX), a novel glycoengineered anti-CD20 monoclonal antibody (mAb), in patients with relapsing forms of multiple sclerosis (RMS) demonstrates rapid and robust B cell depletion (P6. 348). Neurology. 2017;88(16 Supplement):P6. 348
10. Midaglia L, Mora L, Mulero P, Sastre-Garriga J, Montalban X. [Rituximab: its efficacy, effectiveness and safety in the treatment of multiple sclerosis]. Rev Neurol. 2018 Jan 1;66(1):25-32.
11. Naismith R, Piccio L, Lyons J, Lauber J, Tutlam N, Parks B, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis A 52-week phase II trial. Neurology. 2010;74(23):1860-7.
12. Dunn N, Juto A, Ryner M, Manouchehrinia A, Piccoli L, Fink K, et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Multiple Sclerosis Journal. 2017:1352458517720044.
13. Durozard P, Maarouf A, Boutiere C, Ruet A, Brochet B, Vukusic S, Carra-Dalliere C, Labauge P, Mathey G, Debouverie M, Papeix C, Maillart E, Lubetzki C, Bensa C, Gout O, Giannesini C, Stankoff B, Ciron J, Brassat D, Pelletier J, Rico Lamy A, Audoin B; SFSEP and OFSEP groups. Efficacy of rituximab in refractory RRMS. Mult Scler. 2018 May 1:1352458518772748.
14. Yamout BI, El-Ayoubi NK, Nicolas J, El Kouzi Y, Khoury SJ, Zeineddine MM. Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study. J Immunol Res. 2018 Nov 12;2018:9084759.
15. Scotti B, Disanto G, Sacco R, Guigli M, Zecca C, Gobbi C. Effectiveness and safety of Rituximab in multiple sclerosis: an observational study from Southern Switzerland. PLoS One. 2018 May 14;13(5):e0197415.
16. De Angelis F, Tosti ME, Capria S, Russo E, D'Elia GM, Annechini G, Stefanizzi C, Foà R, Pulsoni A. Risk of secondary hypogammaglobulinaemia after Rituximab and Fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study. Leuk Res. 2015 Dec;39(12):1382-8.
17. Perini, P., Calabrese, M., Rinaldi, L. and Gallo, P. The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert Opin Drug Saf 2007; 6: 183190.
18. Amer Awad and Olaf Stüve. Cyclophosphamide in Multiple Sclerosis: Scientific Rationale, History and Novel Treatment Paradigms. Ther Adv Neurol Disord. 2009 Nov; 2(6): 50–61.
19. Comabella, M., Balashov, K., Hafler, D.A., Issazadeh, S., Smith, D., Weiner, H.L. et al. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998; 102: 671678.
20. Karni, A., Balashov, K., Hancock, W.W., Bharanidharan, P., Abraham, M., Kohoury, S.J. et al. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-g production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol 2004; 146: 189198.
21. Chen HJ, Wang CC, Chan DC, Chiu CY, Yang RS, Liu SH. Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass. Send to J Cachexia Sarcopenia Muscle. 2018 Oct 31.
22. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmunity reviews. 2010;9(5):A387-A94.
23. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: when to start, when to change, when to stop? World Journal of Clinical Cases: WJCC. 2015;3(7):545
24. Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P. Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis. Journal of neurology. 2006;253(8):1034-40
25. Alcalá C, Gascón F, Pérez-Miralles F, Gil-Perotín S, Navarré A, Boscá I, Coret F, Casanova B. Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study. J Neurol. 2018 Jul;265(7):1690-1697.
26. Yamout BI, Alroughani R. Multiple Sclerosis. Semin Neurol. 2018 Apr;38(2):212-225.
27. Portaccio, E., Siracusa, G., Piacentini, S., Sorbi, S. and Amato, M.P. Safety and tolerability of cyclophosphamide ‘pulses’ in multiple sclerosis: a prospective study in a clinical cohort. Mult Scler 2003; 9: 446450
2. Dumitrescu L, Constantinescu CS, Tanasescu RSiponimod for the treatment of secondary progressive multiple sclerosis. Expert Opin Pharmacother. 2018 Dec 5:1-8.
3. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1-5.
4. Sellebjerg F, Börnsen L, Ammitzbøll C, Nielsen JE, Vinther-Jensen T, Hjermind LE, von Essen M, Ratzer RL, Soelberg Sørensen P, Romme Christensen J. Defining active progressive multiple sclerosis. Mult Scler. 2017 Nov;23(13):1727-1735
5. Greenfield AL, Hauser SL. B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. 2018 Jan;83(1):13-26.
6. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. New England Journal of Medicine. 2017;376(3):221-34.
7. Lazibat I, Rubinić Majdak M, Županić S. Multiple Sclerosis: New Aspects of Immunopathogenesis. Acta Clin Croat. 2018 Jun;57(2):352-361.
8. Salzer J, Svenningsson R, Alping P, Novakova L, Björck A, Fink K, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. Neurology. 2016:10.1212/WNL
9. Lovett-Racke A, Liu Y, Racke M, Shubin R, Wray S, Su W, et al. Preliminary results of phase 2 multicenter study of ublituximab (UTX), a novel glycoengineered anti-CD20 monoclonal antibody (mAb), in patients with relapsing forms of multiple sclerosis (RMS) demonstrates rapid and robust B cell depletion (P6. 348). Neurology. 2017;88(16 Supplement):P6. 348
10. Midaglia L, Mora L, Mulero P, Sastre-Garriga J, Montalban X. [Rituximab: its efficacy, effectiveness and safety in the treatment of multiple sclerosis]. Rev Neurol. 2018 Jan 1;66(1):25-32.
11. Naismith R, Piccio L, Lyons J, Lauber J, Tutlam N, Parks B, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis A 52-week phase II trial. Neurology. 2010;74(23):1860-7.
12. Dunn N, Juto A, Ryner M, Manouchehrinia A, Piccoli L, Fink K, et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Multiple Sclerosis Journal. 2017:1352458517720044.
13. Durozard P, Maarouf A, Boutiere C, Ruet A, Brochet B, Vukusic S, Carra-Dalliere C, Labauge P, Mathey G, Debouverie M, Papeix C, Maillart E, Lubetzki C, Bensa C, Gout O, Giannesini C, Stankoff B, Ciron J, Brassat D, Pelletier J, Rico Lamy A, Audoin B; SFSEP and OFSEP groups. Efficacy of rituximab in refractory RRMS. Mult Scler. 2018 May 1:1352458518772748.
14. Yamout BI, El-Ayoubi NK, Nicolas J, El Kouzi Y, Khoury SJ, Zeineddine MM. Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study. J Immunol Res. 2018 Nov 12;2018:9084759.
15. Scotti B, Disanto G, Sacco R, Guigli M, Zecca C, Gobbi C. Effectiveness and safety of Rituximab in multiple sclerosis: an observational study from Southern Switzerland. PLoS One. 2018 May 14;13(5):e0197415.
16. De Angelis F, Tosti ME, Capria S, Russo E, D'Elia GM, Annechini G, Stefanizzi C, Foà R, Pulsoni A. Risk of secondary hypogammaglobulinaemia after Rituximab and Fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study. Leuk Res. 2015 Dec;39(12):1382-8.
17. Perini, P., Calabrese, M., Rinaldi, L. and Gallo, P. The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert Opin Drug Saf 2007; 6: 183190.
18. Amer Awad and Olaf Stüve. Cyclophosphamide in Multiple Sclerosis: Scientific Rationale, History and Novel Treatment Paradigms. Ther Adv Neurol Disord. 2009 Nov; 2(6): 50–61.
19. Comabella, M., Balashov, K., Hafler, D.A., Issazadeh, S., Smith, D., Weiner, H.L. et al. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998; 102: 671678.
20. Karni, A., Balashov, K., Hancock, W.W., Bharanidharan, P., Abraham, M., Kohoury, S.J. et al. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-g production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol 2004; 146: 189198.
21. Chen HJ, Wang CC, Chan DC, Chiu CY, Yang RS, Liu SH. Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass. Send to J Cachexia Sarcopenia Muscle. 2018 Oct 31.
22. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmunity reviews. 2010;9(5):A387-A94.
23. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: when to start, when to change, when to stop? World Journal of Clinical Cases: WJCC. 2015;3(7):545
24. Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P. Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis. Journal of neurology. 2006;253(8):1034-40
25. Alcalá C, Gascón F, Pérez-Miralles F, Gil-Perotín S, Navarré A, Boscá I, Coret F, Casanova B. Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study. J Neurol. 2018 Jul;265(7):1690-1697.
26. Yamout BI, Alroughani R. Multiple Sclerosis. Semin Neurol. 2018 Apr;38(2):212-225.
27. Portaccio, E., Siracusa, G., Piacentini, S., Sorbi, S. and Amato, M.P. Safety and tolerability of cyclophosphamide ‘pulses’ in multiple sclerosis: a prospective study in a clinical cohort. Mult Scler 2003; 9: 446450
| Files | ||
| Issue | Vol 57, No 8 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v57i8.2413 | |
| Keywords | ||
| Multiple sclerosis Rituximab Cyclophosphamide | ||
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How to Cite
1.
Etemadifar M, Ghourchian S, Mahinparvar N, Salari M, Etemadifar F, Nikanpour Y, Sanaei S, Akbari M. Cyclophosphamide Versus Rituximab in Progressive Forms of Multiple Sclerosis. Acta Med Iran. 2020;57(8):484-491.
