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Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Moda
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
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.
9. 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
10. 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
11. 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
12. 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
14. 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
15. 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
16. 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
17. 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
19. 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
20. EXPLORER
Conclusion
no difference in efficacy between Placebo and
Rituximab in patients with active SLE treated for
52 weeks
21.
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
29. 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
30. 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.
32. 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
33. “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”.
