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Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
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Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda

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  • 1. L’impiego del Rituximab nel LES Gian Domenico Sebastiani U.O.C. di Reumatologia Azienda Ospedaliera San Camillo-Forlanini Roma 13°Convegno Patologia Immune e Malattie Orfane 2010 Torino, 21-23 gennaio 2010
  • 2. obiettivi terapeutici nel LES sviluppare terapie farmacologiche efficaci nel controllo della risposta autoimmune senza causare effetti tossici inaccettabili
  • 3. © European Working Party on Systemic Lupus Erythematosus
  • 4. Linfocita B • produzione di anticorpi • produzione di citochine • “secondary” antigen-presenting cells antigen- Lipsky : Nat Immunol 2001;2:764 Mizoguchi: J Immunol 2006;176:705 Youinou : Ann NY Acad Sci 2005;1050:19
  • 5. Linfocita B nel LES • linfopenia (cellule B naĩve) naĩve) • alti livelli di plasmacellule “early” e cellule pre-germinative pre- • Espansione di sottopopolazioni cellule B autoreattive Jacobi: J Exp Med 2005; 202: 341 Odendahl: J Immunol 2000; 165: 5970 Yurasov: J Exp Med 2005; 201: 703
  • 6. Rituximab ― la molecola • Anticorpo monoclonale disegnato per colpire ed eliminare solo le B cellule CD20-positive • Rituximab e’ una molecola chimerica – La regione costante, IgG- derivata ha origine umana – La regione variable ha origine murina
  • 7. B cell development Stem Pro-B Pre-B Immature Activated Memory Plasma cells cells cells B cells B cells B cells B cells CD10 Cell surface antigens CD19 CD20 CD24 CD38 CD39 CD22 Roitt et al. Immunology. London, UK: Mosby; 2002; Sell et al. Immunology, Immunopathology, and Immunity. Washington DC: ASM Press; 2001; Silverman et al. Arthritis Rheum 2003;48:1484–1492
  • 8. Retrospective analysis of BCDT in SLE at University College London Hospital: the first 50 patients Study population and clinical assessment • Patients population 50 adult patients with SLE failing conventional immunosuppressive agents • Assessment of clinical outcome – Efficacy (improvement of BILAG score) – Safety (adverse events and laboratory assessments) Lu TY et al. Athritis Rheum 2009;61:482-487
  • 9. Retrospective analysis of BCDT in SLE at University College London Hospital: the first 50 patients Treatment protocol • 1000 mg Rituximab, 750 mg cyclophosphamide, 100-250 100- mg methylprednisolone on 2 occasions 2 weeks apart 35 (78%) patients followed for at least 1 year Lu TY et al. Athritis Rheum 2009;61:482-487
  • 10. Retrospective analysis of BCDT in SLE at University College London Hospital: the first 50 patients RESULTS • 19 (42.2%) total remission, 21 (46.7%) partial remission after 6 months • 5 non-responder non- • significant decrease of anti-dsDNA antibody titer and increase of C3 level anti- • 20 patients no flare • 20/25 patients with flare retreated SAFETY • 5 serious AE: 1 serum sickness-like reaction after Rituximab, 1 death for active SLE, 1 pneumococcal sickness- pneumonia, 1 seizure secondary to hyponatremia, 1 death for ARDS secondary to cyclophosphamide Lu TY et al. Athritis Rheum 2009;61:482-487
  • 11. Retrospective analysis of BCDT in SLE at University College London Hospital: the first 50 patients CONCLUSIONS Combination Rituximab therapy is an effective treatment for patients with active SLE who are nonresponsive to standard immunosuppressive therapy 1 12 Lu TY et al. Athritis Rheum 2009;61:482-487
  • 12. il trial “EXPLORER”
  • 13. Exploratory Phase II/III SLE Evaluation of Rituximab EXPLORER Study population and objectives • Patients population 257 adult patients with moderate-to-severe* extrarenal SLE • Primary objectives – Efficacy (achieving and maintaining a major or partial clinical response) vs placebo infusion at week 52 – Safety (adverse events and laboratory assessments) * assessed by BILAG Merrill JT et al. Athritis Rheum 2010;62:222–233
  • 14. EXPLORER Study design – multicenter, randomized, double blind, placebo controlled Rituximab + Prednisone taper arm open-label retreatment study SCREENING -1W Placebo + Prednisone taper arm Weeks 1 and 3 Week 10 Weeks 24 and 26 Week 52 Days 1 and 15 Study drug infusion (two 1000 mg infusions two weeks apart + 2 further infusions after 6 months) added to prednisone and to baseline immunosuppressive regimen (AZA, MMF, MTX). Prednisone tapered to 10 mg/day by week 10 and to 5 mg/day by week 52 Merrill JT et al. Arthritis Rheum 2010;62:222-233
  • 15. EXPLORER Results • 257 patients, 88 randomized to placebo and 169 to Rituximab • completed the study: 73% placebo and 71% Rituximab • placebo withdravals: 14.8% AE, 10.2% patient/physician decision, 2.2% lost, 0 deaths • Rituximab withdravals: 11.2% AE, 14.2% patient/physician decision, 1.8% lost, 1.8% deaths
  • 16. EXPLORER – CLINICAL RESPONSE AT WEEK 52 80 70 60 50 40 Placebo Rituximab 30 20 10 0 No clinical Partial clinical Major clinical MCR+PCR response response response
  • 17. Immunological parameters
  • 18. EXPLORER Safety • serious adverse events: 36.4% placebo, 37.9% Rituximab • infusion reactions: 8% Placebo vs 13.6% Ritux I ciclo, 4.5% Placebo vs 14.8% Ritux II ciclo • infections: 83% Placebo vs 82.2% Rituximab • serious infections: 17% Placebo vs 9.5% Rituximab • 3 deaths Rituximab: 1 intestinal perforation, 1 multidrug toxicity, 1 unknown
  • 19. EXPLORER Conclusion no difference in efficacy between Placebo and Rituximab in patients with active SLE treated for 52 weeks
  • 20. Rituximab treatment of cyclophosphamide-resistant proliferative Lupus Nephritis Study population and objectives • Patients population 7 adult female patients with severe SLE and lupus nephritis failing conventional immunosuppressive agents including cyc • Objectives – Efficacy (SLEDAI, renal response, histopathologic outcome) – Safety (adverse events and laboratory assessments) Gunnarsson I et al. Athritis Rheum 2007;56:1263-1272
  • 21. Rituximab treatment of cyclophosphamide-resistant proliferative Lupus Nephritis Treatment protocol • Day 0: methylprednisolone 250 mg + cyc 0.5 mg/m2 • Days 2, 9, 16: hydrocortisone100 mg + rituximab 375 mg/m2 • Day 23: methylprednisolone 250 mg + cyc 0.5 mg/m2 + rituximab 375 mg/m2 • oral prednisone 1 mg/kg starting from day 3 with tapering during the following weeks Evaluation of renal rsponse • GFR, urinary sediment, 24 h proteinuria, renal histology (biopsy repeated 3 – 12 months after rituximab treatment) Gunnarsson I et al. Athritis Rheum 2007;56:1263-1272
  • 22. Rituximab treatment of cyclophosphamide-resistant proliferative Lupus Nephritis RESULTS at 6 months • SLEDAI significantly decreased (mean score from 15 to 3) • mean oral prednisone decreased from 18.9 mg/day to 8.3 mg/day • significant improvement of serum creatinine and serum albumin level • significant decrease of anti-dsDNA and anti-C1q antibodies anti- anti- • significant increase of C3 and C4 level • significant decrease of proteinuria • improvement in the histopathologic type in 5/7 (from proliferative to mesangial) with reduction in the renal activity index • 3 patients complete remission and 1 partial remission SAFETY • 1 limited Herpes zoster, 1 photosensitive eruption, 1 neutropenic fever, 1 urinary tract infection Gunnarsson I et al. Athritis Rheum 2007;56:1263-1272
  • 23. Rituximab treatment of cyclophosphamide-resistant proliferative Lupus Nephritis CONCLUSIONS Treatment with Rituximab in combination with CYC was effective and safe in 7 patients with therapy-resistant proliferative lupus nephritis Gunnarsson I et al. Athritis Rheum 2007;56:1263-1272
  • 24. il trial “LUNAR” ACR 2009 Annual Scientific Meeting October 16-21, Philadelphia Efficacy and Safety of Rituximab in Subjects with Active Proliferative Lupus Nephritis Furie R, et al
  • 25. Efficacy and Safety of Rituximab in Lupus Nephritis LUNAR Study population and objectives • Patients population 144 adult patients with class III/IV LN • Primary objectives – Efficacy (achieving and maintaining a complete or partial renal response) vs placebo infusion at week 52 – Safety (adverse events and laboratory assessments) Furie R et al. Athritis Rheum 2009;60:S429
  • 26. LUNAR Study design – multicenter, randomized, double blind, placebo controlled 72 patients Rituximab (Day 1, 15, 168, 182) + MMF + Prednisone 72 patients Placebo (Day 1, 15, 168, 182) + MMF + Prednisone Furie R et al. Arthritis Rheum 2009;60:S429
  • 27. LUNAR Results • 72 patients in each arm with similar baseline features • cumulative response 46% placebo vs 57% Rituximab (p ns) • Rituximab greater effect on anti-dsDNA (p<.01) and C3 (p<.03) • 11% placebo vs 1% Rituximab required another immunosuppressive add on drug • Serious adverse events in 35% placebo vs 30% Rituximab • Infections 16% in both groups – 2 deaths sepsis Rituximab
  • 28. LUNAR Conclusion Although there were more responders with Rituximab, no statistically significant difference between Rituximab + MMF vs Placebo + MMF in patients with active lupus nephritis. Rituximab decreased anti-dsDNA Abs and increased C3 levels.
  • 29. Ramos-Casals M et al. Arthritis Rheum 2009;61:1281-1282
  • 30. Rituximab and Lupus: good in real life, bad in controlled trials • patients with severe disease vs patients with milder disease • patients not responsive to other immunosuppressive therapies • high doses of corticosteroids in “Explorer” and “Lunar” (confounding factor) • ethnic factors may influence the clinical response to drugs • trials require demonstration of superiority of Rituximab over current first line therapy, that is different from clinical practice where Rituximab is given to patients refractory to common immunosuppressors Patients included in “Explorer” and “Lunar” seem to be completely different from those who received Rituximab off-label since 2000 Ramos-Casals M et al. Arthritis Rheum 2009;61:1281-1282
  • 31. “Beliefs, evidence-based medicine and the real life” by Frederic Houssiau • “As scientists, we mostly favour evidence-based therapies; • as human beings, we sometimes favour beliefs; • but as physicians, we always adopt patient- tailored therapies”.

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