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Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie

REFRACTORY MYASTHENIA GRAVIS AND RITUXIMAB: LONG TERM FOLLOW-UP OF 3 PATIENTS AND THE “FORCE” TRIAL. Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie Hôpital Pitié-Salpêtrière, Paris, France. Stem cells. Pro-B cells.

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Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie

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  1. REFRACTORY MYASTHENIA GRAVIS AND RITUXIMAB: LONG TERM FOLLOW-UP OF 3 PATIENTS AND THE “FORCE” TRIAL Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie Hôpital Pitié-Salpêtrière, Paris, France

  2. Stem cells Pro-B cells Pre-B cells Immature B cells Activated B cells Memory B cells Plasma B cells CD10 CD19 CD20 Cell-surface antigens CD24 CD38 CD39 Rituximab(1986) murine antibody fragment IDEC-2B8 human IgG and κ-constant regions

  3. Rituximab in oncology • Rituximab: first mAb for B lymphoma (CD20) • Dose : 375 mg / m2 • Mono therapy, once a week, 4 times. • In association (CHOP), 8 times every 21 days, • More than 1 million treated patients • Few side effects • Progressive multifocal leukoencephalopathy Czuczman et al, 1999; Hainsworth et al, 2002; Leget & Czuczman, 1998, McLaughlin et al, 1999 Smolen et al, ARD 2006; 1-8 ~ 60 cases

  4. Rituximab in autoimmune diseases N Engl J Med, 2004 • Dose: 1g, x2 • Refractory SLE • Refractory vasculitis (cryoglobulin or ANCA) • Pemphigus • Idiopathic thrombocytopenia purpura… Off-label but authorized

  5. IgG monoclonale Chaîne lambda

  6. Rituximab, 375 mg/m2, S0, S1, S2 and S3 with IVIg

  7. Ms H, 37 y. o., MG story • 1987: ptosis, diplopia and muscle fatigue. Anti-AChR +. Treated by pyridostigmine • 1988: Thymectomy, then start of prednisone • 1988-1990: Corticosteroids dependence, start of azathioprine • 1990 – 2000: Honey moon… • 2000: pharyngeal flair, start of IVIg, good response but transient • Dec 2003: first hospitalization in ICU (15 days with invasive ventilation). Prednisone (1 mg/kg/d) + azathioprine + methotrexate • Jan 2004: 2nd ICU, plasma exchanges • Feb 2004: stop azat and MTX for ciclosporine • Apr 2004 – March 2005: IVIg monthly

  8. March 2005 • Evaluation: • Myasthenic Muscle Score (MMS): 30/100 • MGFA class IVb • Great difficulties in daily life (working…) • Nasal voice, 100 ml of water: 25 s. and leaks • Anti-AChR: 140 nM/L • Decision: • 4 plasma exchanges (Anti-AChR: 10 nM/L) • Rituximab, 375 mg/m2, 4 injections (21/03/05 to 14/04/05) • IVIg

  9. Follow-up IVIg IVIg ciclo MFM Azat rituximab x2 Prednisone 110 nM/L HACA -

  10. Ms I, 37 y. o., MG story • 1999: falls and muscle fatigue. Anti-AChR +. Treated by pyridostigmine • 2000: auto-immune neutropenia and anemia • 2001: Thymectomy • 2002: MMS: 75, PN cells: 277/mm3, Hb: 9.2 g/dL ANA + (1/320) with anti-DNA Abs (54 U) => start of prednisone (50 mg/d). • Jan 2003: MMS: 60, start of Azathioprine • Nov 2003: PN cells < 300, stop for MFM but digestive intolerance, start of IVIg • Feb 2004: discoid lupus • May 2005: MMS 60, => start of rituximab (375 mg/m2, x4) after 3 Plasma Exchanges

  11. Follow-up Azat IVIg rituximab 17 nM/L

  12. Mr C, 60 y. o., MG story • 2001: ptosis and muscle fatigue. Anti-AChR Abs +. Treated by pyridostigmine • Aug 2001: Start of prednisone, Azathioprine and IVIg • 2002: MMS: 69 • Sept 2005: MMS: 40, restart of IVIg • Nov 2005: MMS: 40, start of mycophenolate mofetil and plasma exchange • Nov 2005 to April 2006: plasma exchange monthly • April 2006: start rituximab (1g, x2)

  13. Follow-up MMF rituximab 9 nM/L

  14. For how long persist the effects of rituximab? M Dalakas, Nat Clin Pract Neurol, 2008 In trials for RA : 9 months in average

  15. Rituximab and relapse C. Popa et al. Experience with repeated B-cell depletion therapy in RA suggest that ~80% of patients may respond and 50-60% become susceptible to continuing control of the disease.

  16. Human Anti-Chimeric Abs (HACA) and rituximab

  17. Patients with human antichimeric antibody (9.2%) did not exhibit decreasing efficacy or present additional safety concerns.

  18. Can rituximab decrease Ig levels ? C. Popa et al.

  19. And Abs ? N=17 N=16 C Lindholm, J Rheumatol, 2008 KG Smith, Arthritis, 2006

  20. Blood. 2004; 103:4424-8 . • Behavior of factor VIII inhibitor titers in • Patients with a continuous sustained response • Relapsed patients • Nonresponders

  21. MG and rituximab PubMed November 2009 • 11 papers: case reports or short series of patients • 13 patients AChR + • 16 patients MuSK + • 3 seronegative MG K Stieglbauer, J Neurol Sci, 2009

  22. MuSK K Stieglbauer, J Neurol Sci, 2009

  23. I Illa, J Neuroimmunol 2008

  24. I Illa, J Neuroimmunol 2008 J Diaz-Manera, Nat Clin Pract Neurol, 2007

  25. N Zebardast, Muscle Nerve, 2009

  26. Conclusions, perspectives for MG • Only retrospective case reports published • Rituximab seems effective in refractory MG • From 1 to 4 month after the first injection • The effects persist over 6 – 12 months • Patients can be retreated • Waiting for relapse? • Systematical pre-emptive retreatment? • Which dose: complete cycle or 1g only? • Rituximab can decrease the Ab titers • More frequently/rapidly for MuSK / AChR? • Rarely to an undetectable level • 4. Interest in the follow-up of the B cell count (CD19) • No relapse when CD19 remains undetectable… • Need of prospective trials

  27. Rituximab for the treatment of refractory myasthenia gravis (FORCE) Phase II, open, multicentric, prospective study. Reference ClinicalTrial.gov: NCT00774462 Funded by: APHP and AFM Rituximab given by: Roche Principal investigator: O. Benveniste Number of enrolled patients: 11 / 12

  28. Inclusion criteria • 1. Generalised MG • Severe generalised MG, MGFA class IVa, IVb or V • AchR + • 2. Refractory to the conventional treatments • - Resistance to corticosteroids, azathioprine, mycophenolate mofetil, ciclosporine, methotrexate, cyclophosphamide, IVIg and/or plasma exchange. • At least 3 (or more) of these drugs must have been tested. • During > 1 year.

  29. Schedule V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 W-4 to W-1 D-1 D0 D1 M6 M12 M18 D7 D14 D21 1st injection 2nd injection 3rd injection Rituximab: 1000 mg

  30. Outcomes • 1. Main primary: quantitative MG score at M12 • MM Score (range 0-100) • QMG Score (range 0-39) • 2. Secondary • - MG scores at M6 and M18 • MGFA postintervention status • Number of crisis per year • Forced Vital Capacity • Burden of the associated immunosuppressive drugs • Quality of life (SF36) • AChR titer • B cell reconstitution

  31. Acknowledgments Pr Hatron Pr Hachulla Number of enrolled patients: 11 / 12 Pr Levesque Pr Marie Pr Eymard Dr Bolgert Pr Annane Pr Gajdos Pr Sharshar Dr Friedman Pr Farge Pr Rousset Pr Pouget Dr Salort-Campana

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