Transcript B Cell Therapies - Free Online CME Activities | Cleveland

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Advances in B-Cell Biology
in the Treatment of
Autoimmune and
Inflammatory Diseases
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Learning Objectives
• Discuss recent advances in understanding
how B-cell biology affects autoimmune
rheumatic diseases (ARDs)
• Review new biologic agents that target
B cells and their mechanisms of action
• Identify how studies of B-cell–targeted
therapy are changing our understanding
of integrated immune responses and the
pathogenesis of ARDs
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Outline
• B-cell biology in autoimmune disorders
• Overview of B-cell–targeting agents
• Recent developments in B-cell targeting
in rheumatoid arthritis (RA)
• Recent development in B-cell targeting
in other ARDs
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B-Lineage Cells and Autoimmunity
Mature
Bone Marrow
Activation
Blast
Immature
T1
Pro B
Plasma cell
T2
Pre B
Spleen
FO
MZ
Plasmablast
Memory
B
GC
B
T
FDC
DC
Lymphoid
organogenesis
DC
B
TNF-a
IL6
LT
T
M
?
T
Antigen presentation
and costimulation
Inflammatory
cytokines
Autoantibodies
Graves’ disease
Myasthenia gravis
Pemphigus vulgaris
SLE
DC, dendritic cell; FDC, follicular dendritic cell; FO, follicular; GC, germinal center;
(RA)
IL, interleukin; LT, lymphotoxin; Mφ, macrophage; MZ, marginal zone; SLE, systemic
lupus erythematosus; TNF, tumor necrosis factor.
Adapted from Martin F, Chan AC. Annu Rev Immunol. 2006;24:467-496
Multiple sclerosis
Sjögren’s syndrome
RA
Multiple sclerosis
SLE
RA
All autoimmune
disorders
Immune
complexes
SLE
RA
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Why Are Some Plasma Cells
Short-Lived and Others
Long-Lived?
• Plasma cells, which arise after new immune exposures,
are continuously generated in lymphoid tissues, and
perhaps in pathologic ectopic lymphoid tissues
(eg, rheumatoid synovium)
• There are different life expectancies of Ig-secreting
plasmablasts (which can proliferate) and plasma cells
(which cannot proliferate)
• Newly generated plasma cells are released into the
bloodstream, then migrate to the bone marrow
• As long-term survival requires that they find a “niche,”
they must displace “older” plasma cells from their
survival niche for long-term survival
Dörner T, Radbruch A. Immunity. 2007;27:384-392.
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Complex
Interactions
Determine Plasma
Cell Survival
Adhesion
- CD138
- CD44, 18, 11a
- E-/P-selectin
Chemokine systems
- CXCR4/CXCL12
Intracellular survival regulators
- ↑ Bcl-2, Blimp1, XBP1, Aiolos
- ↓ BACH2 and Pax5
Bone marrow
GC
B
Competence
Plasmablasts
Instruction of memory
B cells by T cells
- CD40/154
- ICOS/ICOS-L
- SAP
Long-lived memory plasma cell
Soluble survival factors
- IL-6
- IL-21 (?)
- TNF, IL5
- BAFF/APRIL
Chemokine systems
- CXCR4/CXCL12 (?)
Dörner T, Radbruch A. Immunity. 2007;27:384-392.
Tarlinton D et al. Curr Opin Immunol. 2008;20:162-169.
Insoluble survival
factors from
- nurse cells
- or stromal cells
(within inflamed
tissue)
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Not All CD20+ B Cells Are
Susceptible to Depletion
• Deletion is most efficient in blood
• CD20+ precursors and transitional and naïve B cells appear
highly susceptible to deletion
• CD20+ B1 cells, MZ B cells, and GC B cells are resistant (GC in
GALT Peyer’s patches)
• Most plasma cells are not directly affected by RTX (although in
the tonsil a subset may express CD20)
• Effect of RTX on memory B cells and plasmablasts
– Little is known about RTX effects on these cells in lymphoid organs
• IgG-producing plasma cells generally live longer than IgM
producers
GALT, gut-associated lymphoid tissue.
Gong Q et al. J Immunol. 2005;174:817-826.
Silverman GJ. Arthritis Rheum. 2006;54:2356-2367.
Withers DR et al. Blood. 2007;109:4856-4864.
Terstappen LW et al. Blood. 1990;76:1739-1747.
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Does Extent of Reduction in Synovial
B Cells Explain Clinical Response?
CD22 staining
of synovial tissue
Before Treatment
4 Weeks After Treatment
B-cell depletion
Nondepletion
Vos K et al. Arthritis Rheum. 2007;56:772-778.
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Model of RTX-Induced RA Synovial
Changes in Clinical Responders
BASELINE
B cell
Plasma
cell
T cell
IL-1, IL-6, TNF-a
IFN-g
TNF-a
IFN-g
IL-17
RANKL
RF, anti-CCP antibodies
FLS
Immune complexes
Complement fixation
Induce M secretion
of proinflammatory cytokines
M
TNF-a
IL-1
IL-6
MMPs
Cathepsins
MMPs
Cathepsins
TNF-a, IL-1, IL-6
CCP, cyclic citrullinated peptide; FLS, fibroblast-like
synoviocyte; IFN, interferon; MMP, matrix
metalloproteinase; RANKL, receptor activator of
NF-κB ligand; RF, rheumatoid factor.
Silverman GJ, Boyle DL. Immunol Rev. 2008;
223:175-185.
Osteoclast
Responsible for
marginal erosions
and bone loss
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Model of RTX-Induced RA Synovial
Changes in Clinical Responders
4 WEEKS
X
Early synovial B-cell depletion is
necessary but not sufficient!
Trends toward ↓ in plasma cells in
clinical responders (at 6 months)
B cell
X
Plasma
cell
T cell
IL-1, IL-6, TNF-a
IFN-g
TNF-a
IFN-g
IL-17
RANKL
RF, anti-CCP antibodies
FLS
Immune complexes
Complement fixation
Induce M secretion
of proinflammatory cytokines
M
MMPs
TNF-a Cathepsins
IL-1
IL-6
MMPs
Cathepsins
TNF-a, IL-1, IL-6
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev. 2008;
223:175-185.
Responsible for
marginal erosions
and bone loss
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Model of RTX-Induced RA Synovial
Changes in Clinical Responders
8 WEEKS
Early synovial B-cell depletion is
necessary but not sufficient!
X
Trends toward ↓ in plasma cells in
clinical responders
B cell
X
Plasma
cell
T cell
IL-1, IL-6, TNF-a
IFN-g
TNF-a
IFN-g
IL-17
RANKL
RF, anti-CCP antibodies
Significant ↓ in Ig transcripts in
ACR50/70 clinical responders
(at 6 months)
Trends toward ↓ in lymphocytic
aggregates and T cells
FLS
Immune complexes
Complement fixation
Induce M secretion
of proinflammatory cytokines
M
MMPs
TNF-a Cathepsins
IL-1
IL-6
MMPs
Cathepsins
TNF-a, IL-1, IL-6
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev. 2008;
223:175-185.
Responsible for
marginal erosions
and bone loss
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Model of RTX-Induced RA Synovial
Changes in Clinical Responders
16 WEEKS
Significant synovial B-cell
depletion
XX
B
cell
X
Plasma
cell
T cell
IL-1, IL-6, TNF-a
IFN-g
TNF-a
IFN-g
IL-17
RANKL
RF, anti-CCP antibodies
Immune complexes
Complement fixation
Induce M secretion
of proinflammatory cytokines
X
Significant ↓ in plasma cells
Significant ↓ in T cells and
lymphocytic aggregates
Significant ↓ in CD68+ M
All in clinical responders at
6 months
FLS
M
MMPs
Cathepsins
MMPs
TNF-a Cathepsins
IL-1
IL-6
TNF-a, IL-1, IL-6
?
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev. 2008;
223:175-185.
Responsible for
marginal erosions
and bone loss
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Model of RTX-Induced RA Synovial
Changes in Clinical Responders
24 WEEKS
Primary end point is clinical
response at 24 weeks
XX
B cell
X
Plasma
cell
T cell
IL-1, IL-6, TNF-a
IFN-g
Effects on synovial cytokines/
chemokines have not been
evaluated at later time points
Direct studies on osteoclasts after
RTX are not currently available
TNF-a
IFN-g
IL-17
RANKL
RF, anti-CCP antibodies
Immune complexes
Complement fixation
Induce M secretion
of proinflammatory cytokines
X
FLS
M
MMPs
Cathepsins
MMPs
TNF-a Cathepsins
IL-1
IL-6
TNF-a, IL-1, IL-6
?
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev. 2008;
223:175-185.
Responsible for
marginal erosions
and bone loss
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Insights From RA Synovial
Biopsy Studies
• There are great variations in the histopathologic changes induced
by RTX
• Based on small open synovial biopsy studies, there may be a sequence
of changes in the synovia that leads to clinical response1-6
• B-cell depletion at 4 weeks may predict clinical response; subsequent↓
in plasma cells and Ig transcripts may predict clinical response1,2,5
• RTX-induced depletion of B-lineage cells, with loss of plasma cells and
immune complex formation, may induce clinical responses by multiple
pathways
• B-Cell Roadblock Hypothesis: As B cells are most susceptible to
deletion in the blood, RTX benefits may derive from preventing
reseeding of pathogenic B cells to the synovia7
1. Kavanaugh A et al. Ann Rheum Dis. 2007;66(suppl 2):291 [abstract FRI0037].
2. Rosengren S et al. Ann Rheum Dis. 2007;66(suppl 2):298 [abstract FRI0059].
3. Thurlings RM et al. Ann Rheum Dis. 2008;67:917-925.
4. Dass S et al. Ann Rheum Dis. 2007;66(suppl 2):90 [abstract OP0123].
5. Teng YK et al. Arthritis Rheum. 2007;56:3909-3918.
6. Teng Y et al. Ann Rheum Dis. 2007;66(suppl 2):439 [abstract SAT0034].
7. Silverman GJ, Boyle DL. Immunol Rev. 2008 223:1751-85.
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Conventional Immunosuppressive Therapy
Can Deplete Peripheral Plasmablasts and
Naϊve B Cells, but Not Memory B Cells
CD27
Plasma
cells/blasts
6.7%
2.5%
1.2%
64.0%
72.1%
87.1%
29.2%
25.4%
11.7%
CD27+
memory
B cells
CD19
07/21/03
07/28/03
Methylprednisolone
09/09/03
Cyclophosphamide
Odendahl M et al. J Immunol. 2000;165:5970-5979. Figure courtesy of T. Dörner (Berlin, Germany)
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Are There Predictive Biomarkers of
Response to RTX Treatment in RA?
• Open trial of 17 patients with refractory RA who
received a first cycle of rituximab
• 12 patients responded with good EULAR responsesa
– 6 patients with an early relapse (weeks 24–40)
– 6 patients with a late relapse (after week 40)
• 5 patients were classified as nonresponders
• 1 patient remained in remission after 1 cycle of
treatment
• 11/17 patients received a second cycle of rituximab
– 2/11 were RF-negative, 3/11 were anti-CCP–negative
Roll P et al. Arthritis Rheum. 2008;58:1566-1575.
was defined as improvement in DAS28 ≥1.2.
DAS28, Disease Activity Score including a 28-joint count; EULAR, European League Against Rheumatism.
aResponse
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At Baseline, Higher CD27+ Memory B Cell Counts Correlated With
Early Relapse in Clinical Responders After RTX Treatment
CD27+ B cells/µL Before Therapy
CD27
60.0
memory
50.0
40.0
30.0
20.0
naive
10.0
IgD
P = .045
0.0
Early Relapse
Memory B cells are either IgD+ or IgD-
(Week 24–40)
Late Relapse
(After Week 40)
At Time of B-cell Regeneration, Clinical Nonresponders Had Higher Levels of
IgD+ CD27+ Memory B Cells – Lack of Persistent Memory B Cell Reductions
CD27+/IgD+ B cellsa
CD19+/CD27+ B Cells/ml
2.0
P = .019
0.0
Responder
(n = 12)
aFirst
Roll P et al. Arthritis Rheum. 2008;58:1566-1575.
Nonresponder
(n = 5)
time-point of regeneration
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Summary
• In RA, levels of CD27+ memory B cells increase with disease
duration1
• After RTX treatment, at time of B-cell regeneration, clinical
nonresponders had higher levels of IgD+ CD27+ memory B cells
– Lack of lasting memory B cell reductions
• Early relapse after the first RTX cycle was associated with higher
CD27+ memory B cell counts prior to therapy and higher IgD+/CD27+
and IgD-/CD27+ B cell counts after first and second treatment cycle,
compared with late-relapsing patients
• Yet even for nonresponders after the first cycle, RTX retreatment
can still be effective
• Clinical response to anti-CD20 treatment may be primarily
dependent on the reduction of blood memory B cells,
and this may be linked to a reduction of plasmablasts
1. Fekete et al. J Autoimmun. 2007;29:154-163.
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Epratuzumab: A Humanized
Anti-CD22 Therapeutic Antibody
• CD22 first appears on B cells at the stage of antigen responsiveness
• CD22 acts as a coreceptor with the antigen receptor that can downregulate antigen responses
• Interacts with inhibitory a2,6-linked sialic acid–associated
glycoproteins
• Epratuzumab induces rapid CD22 internalization and phosphorylation
• In clinical trials for ARD and NHL
• Open phase I trial in 12 patients with SLE showed safety and some
efficacy based on BILAG scores
– All patients fulfilled ACR criteria
– Majority of patients had low disease activity (median SLEDAI = 2)
How does epratuzumab work?
What are the effects on the human immune system?
BILAG, British Isles Lupus Assessment Group; ACR, American College of Rheumatology;
NHL, non-Hodgkin‘s lymphoma; SLEDAI, systemic lupus erythematosus disease activity index.
Dörner T et al. Arthritis Res Ther. 2006;8:R74. doi:10.1186/ar1942.
Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.
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Epratuzumab Preferentially Reduced Peripheral
Blood Naϊve B Cells; Plasmablasts and CD27+
Memory B Cells Are Less Affected
B cells
absolute cell number
CD27- naive B cells/ml
CD27+ memory B cells/ml
CD27++ plasmablasts/ml
Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.
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Epratuzumab Modulates the
Activation and Proliferation of
B Cells in Patients With SLE
• Epratuzumab was shown to be safe in a phase I open trial
• Surface levels of CD22 were rapidly down-modulated
• Average reduction of 30% of total blood B-cell levels, that
lasted for 12 weeks after last infusion
• Reductions primarily in naïve B cells, trend to increase in
plasmablasts. No change in memory B cells
• Laboratory studies show epratuzumab causes impaired B-cell
proliferative responses to in vitro experimental stimulation
of T-cell–independent pathway
• CD22-targeted therapy may provide mechanistic advantages
in patients with certain autoimmune diseases
• More studies are warranted
Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.
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Conclusions
• Studies with RTX have demonstrated an attractive
safety/efficacy profile in RA and encouraged the development
of newer agents
• A diversity of additional strategies for targeting B cells, as well
as design of biologic agents, are currently under investigation
• Different B-cell subsets, including naïve B cells, plasma
cells/blasts, and memory B cells, appear to make different
contributions to pathogenesis
• The capacity to inhibit or delete each B-cell subset varies
greatly based on the mechanism of action of the therapeutic
agent
• Investigations into B-cell–targeted therapy are providing
new therapeutic options as well as helping to elucidate
previously unknown immunologic mechanisms of
pathogenesis.
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B-Cell–Directed Therapy
for RA
RA, rheumatoid arthritis.
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Learning Objectives
• State the rationale of B-cell depletion for the
management of RA and list at least 3 agents that
are being studied in clinical trials
• Summarize the efficacy of B-cell–targeted therapy
following DMARD and anti-TNF therapy failure
• Describe the safety of long-term and repeated
courses of B-cell–targeted therapy and the
nuances of fixed or on-demand retreatment
• Summarize the radiographic changes noted
following B-cell–targeted therapy for RA
DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.
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CD20: A Target on B cells
• 297-AA membrane-associated
phosphoprotein (33–37 kDa)
• Not shed: No known
membrane/secreted molecular
analogues
TRU-015
Ofatumumab
Ocrelizumab
• Selective expression: Not
expressed on stem cells, pro-B
cells, plasma cells, dendritic cells
• Anti-CD20 binding:
– Does not rapidly modulate
expression
– Does not cause substantial
internalization
CD20
• Differences in epitope binding are
of unclear clinical significance with
regard to safety or efficacy
AA, amino acid.
Kehrl JH et al. Immunol Today. 1994;15:432-436; Golay J et al. Blood. 2000;95:3900-3908.
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RTX (REFLEX): EULAR Responses
Based on RF/Anti-CCP
RF/Anti-CCP+
(Either or Both)a
% Patients EULAR Mod/Good
80
RF/Anti-CCP−b
75
70
60
50
44
40
30
29
20
• While significantly more
patients receiving RTX
demonstrated ACR20
and EULAR responses
compared with placebo
recipients, seronegative
patients (for RF and
anti-CCP) did not
respond as well
14
aP
10
bP
> .0001 vs placebo, seropositive.
= .05 vs placebo, seronegative.
0
Placebo
RTX
Placebo
RTX
Anti-CCP, anti–cyclic citrullinated peptide; EULAR, European League Against Rheumatism;
RF, rheumatoid factor.
Tak PP et al. Ann Rheum Dis. 2007;66(suppl 2):338 [abstract FRI0192].
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Repeated Treatment With RTX Produces
Sustained Efficacy in Patients With RA
With an Inadequate Response to DMARDs
Week 24 (n = 57)
Patients (%)
80
70
Course 1
60
Course 2
50
Course 3
40
30
20
10
0
ACR20
ACR50
ACR70
DAS28 ≤ 3.2
(Low Disease
Activity)
DAS28 < 2.6
(Remission)
DMARD, disease-modifying antirheumatic drug; DAS28, Disease Activity Score including a 28-joint count.
Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].
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Placebo
60
Patients (%)
50
a
Rituximab
40
30
20
a
a
10
0
ACR 20 ACR 50 ACR 70
Patients (%) Achieving MCID
Patient-Reported Outcomes During RTX
Treatment of Anti–TNF-a Refractory RA
in Addition to ACR Responses
Placebo + MTX (n = 201)
100
RTX + MTX (n = 298)
80
a
a
a
60
40
20
0
FACIT-F
HAQ-DI
PCS
MCS
aP
< .0001 vs placebo + MTX.
MCID, minimum clinically important difference; FACIT-F, Functional Assessment of Chronic Illness
Therapy–Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; PCS, physical component
score; MCS, mental component score.
Cohen SB, et al. Arthritis Rheum 2006;54:2793-2806. Keystone E et al. Arthritis Rheum. 2008;59:785-793.
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Repeated Treatment With RTX Produces
Sustained Efficacy in Patients With an
Inadequate Response or Intolerance to
TNF Inhibitors
Patients (%)
Week 24 (n = 96)
80
70
60
50
40
30
20
10
0
Course 1
Course 2
Course 3
ACR20
ACR50
ACR70
Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].
DAS28 ≤ 3.2 DAS28 < 2.6
(Low Disease (Remission)
Activity)
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REFLEX: Change in Radiographic
Outcomes at Week 56
P = .0046
2.5
2.31
Placebo (n = 184)
RTX (n = 273)
Mean Change
2
1.5
1.32
1
1
0.99
0.59
0.41
0.5
0
TGS
JSN
JSN, joint space narrowing; TGS, total Genant-modified Sharp score.
Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0011].
Erosion Score
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REFLEX: Change in Radiographic
End Points at Week 56
Change in Sharp–Genant Total Score at
Week 56 by Anti-CCP Status at Baseline1
4
2.75
Placebo
RTX
3.5
2.5
2.21
3
2
1.5
1
1.19
1.09
0.97
0.85
Mean Change
Mean Change in X-ray Score
3
ACR20 Nonresponders at Week 242
Placebo (n = 104)
RTX (n = 87)
2.82
2.5
2
1.72
1.5
1.1
1
0.66
0.5
0.5
0
0
(n = 11) (n = 78) (n = 21) (n = 33) (n = 85) (n = 129)
Missing
Negative
Positive
0.33
TGS
JSN
0.33
Erosion Score
The effect of RTX in inhibiting joint damage was consistent for all subgroups examined
(baseline: total Sharp score, DAS28, disease duration, CRP, HAQ, SJC, and TJC). The study
was not powered to detect treatment differences within each subgroup; however, numerically
similar and consistent results were observed for nearly all subgroups analyzed.
CRP, C-reactive protein; SJC, swollen joint count; TJC, tender joint count.
1. Cohen S et al. Ann Rheum Dis. 2007;66(suppl 2):428 [abstract SAT0002].
2. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0012].
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REFLEX: RTX Radiographic
Findings in RA at 2 years
4
• Total Genant-modified Sharp
score used
3
• Effects on JSN and erosions
were similar
• 87% of RTX patients who did
not progress in year 1, did not
progress in year 2
• The data are confounded by
multiple therapeutic changes
RTX
Placebo
(n = 187) (n = 281)
2.81
1.78
2
1.14
1
0.66
0
Year 1
80
No  TGS (%)
– Linear extrapolation used for
missing week 104 x-rays
(30% of patients)
TGS
• X-rays at weeks 0, 24, 56, 104
60
RTX
60
Year 2
Placebo
46
68
54
40
20
0
Cohen S et al. Ann Rheum Dis. 2008;67(suppl 2):189 [abstract THU0167].
Baseline to
1 Year
1 Year to 2 Years
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RTX Fixed Retreatment vs
On-Demand Retreatment of RA
• Fixed and on-demand retreatment with RTX showed equal efficacy and
safety
• Fixed retreatment was more effective in moderate responders and
nonresponders to the first course
• Nonresponders improved significantly only after fixed retreatment
70%
Patients (%)
60%
64%
53%
Fixed Retreatment
50%
40%
On-Demand
Retreatment
28%
30%
18%
20%
10%
4%
6%
0%
ACR 20
ACR 50
ACR 70
Teng Y et al. Ann Rheum Dis. 2008;67(suppl 2):339 [abstract FRI0167].
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Switching Strategies When an
Anti–TNF-α Fails: RTX or
Alternate Anti–TNF-α
Type of Prior Anti–TNF-α Failure
Overall (%)
65
35
0
Switch to alternate anti-TNF-α (%)
• Adalimumab
• Etanercept
• Infliximab
56
25
19
Significance
• Overall evolution of DAS 28 more
favorable in RTX vs alternate
anti–TNF-α
• Concomitant DMARD use
• Type of anti–TNF-α agent switch
• Type of prior anti–TNF-α failure
–Efficacy
–AEs
P = .01
NS
NS
(Graph)
I
M
P
R
O
V
E
M
E
N
T
DAS 28 Δ From Baseline
• Not effective
• ≥AE
Signif
NS
Not Effective
AEs
Significant
Not
significant
-0.5
-0.77
-0.86
-1
-1.03
-1.5
-1.55
RTX (n = 101)
Switch anti–TNF-α
agent (n = 199)
-2
N = 300.
Finckh A et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0249].
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Subsequent RTX Treatment Courses:
Incidence of Acute Infusion Reactions
by Treatment Course
Patients (%)
100
First infusion
80
Second infusion
60
40
20
23
7
11
2
0
Course 1 (n = 1053)
Course 4 (n = 142)
• SIEs occurred in <1% of patients during course 1 and 2
• No SIEs were observed during course 3 or 4
All-exposure population by treatment course.
SIE = serious infusion-associated event.
van Vollenhoven RF et al. Arthritis Rheum. 2007;56(9 suppl):S147 [abstract 257].
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Design of B-Cell–Targeting Agents
Chimeric antibody
Mouse (red)
(Synthetic) fully human antibody
Human variable regions
Human
Rituximab (CD20)
SMIP
Human IgG constant region
Ocrelizumab (CD20)
Ofatumumab (CD20)
Belimumab (BAFF)
Epratuzumab (CD22)
Mouse (red)
Synthetic peptide
Decoy receptors
Human
TRU-015 (CD20)
Atacicept
(BAFF and APRIL)
(TACI-Ig)
BR3-FC
(BAFF)
Human (green)
Baminercept-alpha AMG623
(LT-)
(BAFF)
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Therapeutic Approaches
to B-Cell Depletion
Memory Cell
Stem
Cell
ProB Cell
PreB Cell
Epratuzumab (Anti-CD22)
Immature
B cell
Transitional
B cell
Mature
B cell
Antigen
stimulation
Antibody-producing
Plasma cells
CD19
Modulates B cell function
With limited depletion
RTX (anti-CD20)
Binds and eliminates
CD20-positive cells
Autoreactive B
cells
SLE
RA
Other diseases
Belimumab (antisoluble BAFF)
Acts later in B-cell development
Potently depletes Ig-secreting cells
Atacicept (TACI-Ig)
Neutralizes both BAFF and APRIL
Acts broadly in B-cell development
Potently depletes Ig-secreting cells
SLE, systemic lupus erythematosus.
41
Therapeutic Approaches to B-Cell
Depletion: Clinical Trial Status
Description
Indications
Approved
Rituximab
Chimeric anti-CD20
RA
Ocrelizumab
Humanized anti-CD20 antibody based on RTX
RA
Belimumab
Human antibody that binds/sequesters BAFF/BLyS,
B-cell survival factor
SLE
Epratuzumab
Humanized anti-CD22 antibody
SLE
Baminercept Alfa
Soluble LTß receptor IgG1 fusion protein
RA
TRU-015
Anti-CD20 SMIP (small modular
immunopharmaceutical)
RA
Ofatumumab
Human IgG antibody from humanized transgenic mice
RA
Phase 3a
Phase 2a
aStatus
as of July 17, 2008.
42
Ocrelizumab (OCR):
Humanized
Anti-CD20 mAb in RA
• Phase I/II dose-escalation RCT
with OCR + MTX
70
58
60
Patients (%)
– 175 patients in whom 1–6
DMARDs failed
– ≥8 TJC and SJC plus CRP
≥1 mg/dL or ESR ≥28 mm/h
– Single infusion of OCR
(400, 1000, 1500, or
2000 mg) or placebo
– No peri-infusional
corticosteroids
ACR Results at Week 24
Placebo
58
OCR 400
OCR 1000
50
40
OCR 1500
38
34
27
30
• 1° end point: ACR20 at
week 24
10
• Complete peripheral B-cell
0
depletion
• Patients with incomplete response
require 100 mg IV corticosteroids
OCR 2000
33
32
23
25
19
20
14 13
9
3
ACR20
ACR50
ESR, erythrocyte sedimentation rate; IV, intravenous; OCR, ocrelizumab; mAb, monoclonal antibody;
RCT, randomized controlled trial.
Tak PP et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0250].
0
ACR70
43
CD20 – Ofatumumab: Human
Anti-CD20 IgG1 mAb – Phase II Study
ACR20
ACR50
ACR70
60
49
Patients (%)
50
46
Placebo
300
700
1000
AE (%)
57
81
84
83
SAE (%)
4
7
9
11
SIE (%)
4
2
0
4
41
40
b
30
26
26
a
20
10
19
• Conclusions
15
9
5
4
6
0
0
Placebo
n = 55
300
700
1000
n = 58
n = 57
n = 54
aP
< .05;
bP
– No apparent dose response
– No limiting safety signals as yet
<.01
Østergaard M et al. Arthritis Rheum. 2007;56(9 suppl):S793-S794 [abstract 2086].
45
TRU-015 in Patients With RA:
Phase II Dose-Ranging Study
• 24-week double-blind RCT in
patients with incomplete
response to MTX
• 227 patients in United States
– ≥6 tender joints and swollen
joints; RF+
– Either increased ESR/CRP
or morning stiffness >45 min
• 1 infusion, TRU-015 or placebo
– 200, 400, 800, or 1600 mg
– Premedicated
• 1 grade 3 AE on infusion day
(400-mg group)
• Conclusion: 800 and 1600 mg
of TRU-015 IV once statistically
superior to placebo at week 24
Pbo
200
400
800
1600
n = 53
n = 56
n = 57
n = 53
n = 57
2
2
5
2
4
−1.2
−1.6
−1.6
−2.1a
−2a
ACR20%
33
49
37
65b
61c
ACR50%
9
19
16
26a
13
ACR70%
2
6
6
0
4
−0.37
−0.5
−0.5
−0.64
−0.7
28
38
42
47
48
SAE (%)
DAS28
∆ HAQ
%↓ CRP
aP
< .05; bP = .003; cP = .008.
Burge D et al. Abstract presented at: ACR/ARHP Annual Scientific Meeting; November 6–8, 2007;
Boston, Massachusetts; abstract L7.
46
LTβR-Ig (Baminercept)
• Human lymphotoxin- receptor (LT) extracellular domain fused to
human IgG1 Fc receptor acts as a decoy receptor for LT
• Effective in murine models of arthritis:
– Blocks induction of arthritis and decreases severity of arthritis in established disease
B cells, T cells,
NK cells
Activated T cells
Dendritic cells
LIGHT Pathway is implicated in:
• Mucosal and hepatic inflammation
LIGHT
Lymphotoxin a/ Pathway is
implicated in:
• Liver, spleen, and lymph nodes
• Gut mucosa and Peyer’s patches
LTa
Baminercept alfa
HVEM
LTR
T Cells
B cells
NK cells
Costimulation of T-cell activity
• Affects T-cell responsiveness (proposed) and enhanced survival
HVEM, herpes virus entry mediator.
Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].
Control of Lymphoid
Microenvironments
48
LTβR-Ig (Baminercept) in RA
• Placebo dose-finding Phase IIa RCT: 47 pts – IR ≥1 DMARD; +MTX
• SC weekly injections x4 and observation to day 77:
– 6 dose cohorts: 0.01, 0.05, 0.1, 0.3, 1 and 3 mg/kg BAM versus PBO
• AEs >5%: PBO 55% and LTβR-Ig 67%
– Headache: Placebo 9% and LTβR-Ig 19%
– Flu-like symptoms in 25% within 24 h of first injection; ↓ with subsequent injections to 6–9%
Patients (%)
• Continued clinical responses after week 4 despite discontinuation of treatment
• Phase IIb planned: 5, 50, 200 mg weekly
80
70
60
50
40
30
20
10
0
mg/kg
Sample size:
ACR20
ACR50
ACR70
67
50
50
40 40
30
25 25
0 0
50
33
20
33
17
0 0 0
0 0 0
PBO
BAM 0.01
BAM 0.05
BAM 0.1
BAM 0.3
BAM 1.0
BAM 3.0
10
6
6
4
5
6
6
Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].
49
Summary
• B-cell–directed therapy has demonstrated
clinical and laboratory efficacy in RA
• Multiple other diseases potentially may be
treated with B-cell–directed therapy
• Safety issues concerning long-term B-cell
depletion are of concern, but data thus far are
cautiously reassuring
• New strategies of B-cell targeting may provide
more potent therapeutics in the future
50
Assessing
Immunocompetence in
Patients Treated With
B-cell–Directed Therapies
51
Learning Objectives
• Define immunocompetence and review the impact
of B-cell–directed therapies on humoral immunity
• Summarize the safety of B-cell–directed therapies
with regard to the following clinical scenarios:
repeated use, safety of switching to DMARD or TNF
inhibitor after RTX failure, effects on serum
immunoglobulins, and serious infection rates
• State clinical considerations for immunizing patients
who are candidates for B-cell–directed therapy
DMARD, disease-modifying antirheumatic drug; RTX, rituximab; TNF, tumor necrosis factor.
52
Outline
• Immunocompetence and the effects of B-cell–
directed therapies
• Safety of B-cell–directed therapies
–
–
–
–
Long-term safety of repeated use
Effects on serum immunoglobulins
Serious infection rates
Safety of switching to DMARD or TNF inhibitor after RTX failure
• Immunization and B-cell–directed therapy
• Considerations for immunocompetence of newer
B-cell– targeting agents BAFF, APRIL
• Progressive multifocal leukoencephalopathy (PML)
in rheumatic diseases
53
Defining Immunocompetence:
Promises and Problems With
Biologic Therapies
• Immunocompetence is broadly defined as the
capacity of the integrated immune response to
defend against infections and malignancies
• An increased rate of infections is the gold
standard for detecting compromised immune
function, but:
– Clinical trials are generally underpowered for rare
events
– Data collected across clinical trials and databases
of such events are not uniform
54
Immunocompetence and
B-Cell–Directed Therapy
Pro-B
Pre-B
Immature
Transitional
Naïve
Memory
CD20
• Humoral immunity is vital in
protecting the host from
bacterial infections
RTX
Protective vs
pathogenic antibodies
Plasmablast
(short-lived)
Plasma Cell
(long-lived)
Protective vs
pathogenic antibodies
Antimicrobial
Antimicrobial
Anti-dsDNA
Anti-dsDNA
RF and anti-CCP
antibodies
Anti-RBP antibodies
(Ro, La, Sm/RNP)
Survive weeks after
RTX
Survive months to
years after RTX
RTX spares long-lived plasma cells,
which are the primary source of
antimicrobial Abs
• Patients deficient in Ab are
prone to polysaccharide
encapsulated bacterial
infections
• Experience in oncology fails to
show that RTX adds risk of
SIEs to traditional
chemotherapy (except in HIV
infections)
Ab, antibody; CCP, cyclic citrullinated peptide; dsDNA, double-stranded DNA; HIV, human immunodeficiency
virus; RF, rheumatoid factor; SIE, severe infectious event.
Looney RJ, et al. Arthritis Rheum. 2008;58:5-14.
55
Immunoglobulin Levels
Following RTX Therapy
• Total immunoglobulin (Ig), IgM, IgG
– Every 8–12 weeks after each course
• Always normal IgG & IgM: 761 (72%)
– >1 Ig level <LLN (at any point)
• >1 low IgM: 261 (25%)
• >1 low IgG: 67 (6%)
Percent of Patients IgM/IgG <LLN
24 Weeks After RTX
C1
C2
C3
C4
IgM
10.1
20.4
20.9
31.4
IgG
1.4
3.5
4.0
4.3
SIEs per
100 pt-yr
5.4
4.6
6.3
5.4
• Decreases are nonprogressive in most cases
• Patients undergoing repeated courses of RTX have been reported
with severely depressed IgM levels, but background therapy has
been nonstandardized and has included CTX
CTX, cyclophosphamide; LLN, lower limit of normal.
Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261].
Popa C et al. Rheumatology (Oxford). 2007;46:626-630.
56
Long-Term Safety of RTX
With Repeated Use
• 1053 patients (2438 patient-years) from 3 double-blind trials
–
–
–
–
1014 >6 months
957 >1 year
701 >2 years
120 >3 years
• Up to 7 treatments (1000 mg  2 IV, 2 weeks;
≥4 months from last infusion)
– 684 ≥2 courses; 400 ≥3 courses; 142 ≥4 courses
• Acute infusion reactions decreased with subsequent courses
– 1st infusion: C1, 23%; C4, 11%
– 2nd infusion: C1, 7%; C2, 2%
• 702 (67%) had ≥1 infection
– URI: 32%; UTI: 11%
• No tuberculosis, opportunistic infections, or viral reactivation
• 36 malignancies in 32 patients (3%): 4 fatal; no lymphomas
C, course; URI, upper respiratory tract infection; UTI, urinary tract infection.
van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].
57
Long-Term Safety of RTX
With Repeated Use
Safety of Additional Courses of RTX in Patients With Active RA:
Open-Label Extension Analysis
C1
C2
C3
C4
AEs
4570
1358
339
48
SAEs
222
73
18
3
Infections
954
347
71
11
Infections per 100 pt-yr
83
83
80
88
SIEs
59
19
5
1
SIE per 100 pt-yr
5.1
4.6
5.6
8.0
A total of 1,039 patients received >1 course of rituximab. Of these, 570 received 2 courses,
191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years.
AE, adverse event; RA, rheumatoid arthritis; SAE, serious adverse event.
Keystone E et al. Arthritis Rheum. 2007;56:3896-3908.
58
Serious Infection Rates by
Immunoglobulin Levels With
Repeated Use of RTX
All-Exposure
Population
(n = 1053)
Patients With
Normal IgG
and IgM
(n = 761)
Patients with Patients With
Low IgM at
Low IgG at
Any Time
Any Time
(n = 261)
(n = 67)
Percentage of
patients, %
100
72.2
24.7
6.3
Serious
infections per
100 pt-yr
(95% CI)
5.4
(4.3–6.38)
4.9
(3.93–6.06)
6.4
(4.74–8.68)
6.8
(4.03–11.49)
Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261].
59
Long-Term Safety of RTX
With Repeated Use
Conclusion
• A progressive increase in the number of patients who
have ≥1 Ig level below LLN is seen at some point with
repeated infusions of RTX
• The rate of infections has been stable
• RTX should be used with caution in patients previously
treated with biologics, and long-term studies are needed
• A more complete safety profile of RTX will emerge as
more patients are treated, followed up for longer periods
of time, and given more courses of RTX
van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].
60
Rate of Serious Infections With
Rituximab and Other RA Therapies
Incidence of Serious Infections per 100 Patient-Years
Rituxan-exposed patients (n=1053)
Biologic-treated patients (n=9868)
(BSR Biologics Register)
Biologic-treated patients (n=928)
(German Biologics Register)
DMARD-treated patients (n=1352)
(BSR Biologics Register)
DMARD-treated patients (n=601)
(German Biologics Register)
0
2
4
BSR, British Society for Rheumatology.
van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].
Listing J et al. Arthritis Rheum. 2005;52:3403-3412.
Dixon WG et al. Arthritis Rheum. 2006;54:2368-2376.
6
8
10
61
Safety of Switching to DMARD or
TNF Inhibitor After RTX Failure
All Patients
DMARDs Added
TNF Inhibitor Added
Before
After
Before
After
Before
After
143
148
50
42
101
98
28 (40)
24 (35)
NR
NR
NR
NR
SIEs, no.
6
12
1
2
6
9
SIE/100 pt-yr
4
8
2
5
6
9
1.9–9.4
4.6–14.9
0.3–14.2
1.2–19
2.9–19.3
4.8–17.7
Total exposures, pt-yr
SAEs/100 pt-yr (n = 75)
95% CI
• 153 patients (of 1053) withdrew from RTX extension studies
• Entered safety follow-up for up to 48 weeks for SAEs
– Could be treated with DMARD(s) or TNF inhibitor
– 107 (70%) treated with TNF inhibitor and 46 (30%) DMARD(s)
– Majority had CD19 counts <LLN
• 18 SAEs were infectious – typical clinical course – resolved with treatment
• Conclusion: No increased SIEs demonstrated with switching to
DMARD/TNF inhibitor
– “Further investigations in larger numbers over time is warranted”
Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S150 [abstract 262].
63
Can Patients Given Biologics,
Including B-Cell–Depleting
Therapy, Be Effectively
Immunized?
64
Immunization and
Immune Response
• Responses to immunization depend on intact
immune response
– T-cell–dependent antigens (peptide)
– T-cell–independent (carbohydrate)
– Response to neoantigens
– Response to recall (booster) antigens
• How do newer targeted immunomodulatory
therapies affect immunization responses?
65
Biologics and Immunization
• TNF antagonists may slightly decrease immune
response to influenza immunization compared with
MTX1
• B-cell depletion in RTX-treated patients with SLE
significantly decreased response to pneumococcal
vaccine and tetanus immunization in almost all
patients, although partial responses were observed
on return of peripheral B cells2
• Abatacept decreased response to neoantigens
(X174 and KLH) in patients with psoriasis3
KLH, keyhole limpet hemocyanin; MTX, methotrexate; SLE, systemic lupus erythematosus.
1. Kapetanovic MC et al. Rheumatology (Oxford). 2007;46:608-611.
2. Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323].
3. Abrams JR et al. J Clin Invest. 1999;103:1243-1252.
66
Response to Influenza Vaccine
in RA Treated With Abatacept
Proportion of Patients Responding* to Different
Numbers of Influenza Serotypes –
1 Month Post-immunization
Positive Responders (%)
• Previous data suggest that
abatacept may blunt response to
the T-cell–independent Ag
pneumococcus in healthy controls
and patients with RA
• Influenza is a T-cell–dependent
Ag, with healthy individuals
demonstrating seroconversion
(4-fold) to 33%–44% of the time
• ARRIVE trial studied abatacept in
patients in whom TNF inhibitors
failed
• Substudy of 21 patients given
influenza vaccine 7 days prior to
abatacept in patients receiving
long-term therapy
90
75%
80
70
60
50%
50
40
30
25%
15%
20
10
0
0
≥1
≥2
3
Number of influenza strains responded
• 75% of patients mounted an adequate response to
at least 1 strain 1 month post-vaccination; 50%
to 2 strains; 15% to all 3
• MTX, consistent with previous studies, blunts
response
• Abatacept does not appear to meaningfully
impair response to influenza
*Positive response defined as post-immunization antibody titer at least 4 times above baseline value.
Ag, antigen; ARRIVE, Abatacept Researched in RA Patients With an Inadequate
Anti-TNF Response to Validate Effectiveness.
Schiff M et al. Arthritis Rheum. 2007;56(9 suppl):S392 [abstract 943].
67
RTX and Vaccination
• Following RTX administration,
post-vaccination protection rates
are decreased in response to
– Pneumococcal vaccine1
– Tetanus toxoid1
– Trivalent influenza vaccine2,3
1. Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323].
2. Gelinck L et al. Ann Rheum Dis. 2007;66(suppl 2):160 [abstract THU0116].
3. Oren S et al. Ann Rheum Dis. 2007;66(suppl 2):363 [abstract FRI0275].
68
Immunization Responses With
RTX in Patients With RA
• 4 patients treated with RTX (1000 mg  2)
– Immunization with trivalent influenza A/B at 84
days during B-cell depletion
• 19 patients receiving TNF antagonists
• 20 healthy controls
• Evaluation of preimmunization and
postimmunization titers to antigens
Gelinck LB et al. Ann Rheum Dis. 2007;66:1402-1403.
69
RTX Impairs Ability to Respond to
Influenza Vaccine in Patients With RA
A/H3N2
GMT
256
128
64
32
16
Influenza B
1024
1024
512
512
Post-vaccination
512
HC
RA - TNF
RA - RTX
Pre-vaccination
1024
A/H1N1
256
128
64
32
16
8
256
128
64
32
16
8
4
4
8
2
2
4
1
Pre
Post
Vaccination
Response Defined
as GMT
> 40 units
1
Pre
Post
Pre
Vaccination
RA-RTX
RA-TNF
HC
N=4
N = 19
N = 20
A/H3N2 (%)
50
84
100
A/H1N1 (%)
23
84
88
Influenza B (%)
24
84
96
GMT, geometric mean titers; HC, healthy controls.
Gelinck LB et al. Ann Rheum Dis. 2007;66:1402-1403.
Post
Vaccination
70
Immunization: Summary
• Consider immunization responses when treating patients with RA
and when introducing new targeted therapies
• Live attenuated virus vaccines should be avoided in all patients
receiving immunosuppressants (based on absence of data)
• Some immunomodulatory therapies may significantly attenuate
the efficacy of other immunizations
• Timing of immunizations may be clinically important
• Evaluating larger numbers of patients treated with these agents
alone and in combination with other DMARDS and concomitantly
evaluating appropriate controls using standardized definitions of
response are very important in guiding clinical care
• Appropriate immunization should be performed prior to
initiation of RTX therapy
Gelinck LB et al. Ann Rheum Dis. 2007;66:1402-1403.
71
PML in Rheumatic Diseases
• PML is a neurologic disease caused by infection with the JC polyomavirus
that occurs in susceptible patient populations
• Recently reported in 0.1% of patients receiving natalizumab, a promising
drug for multiple sclerosis (also in clinical trials for RA and Crohn’s disease)
• Mechanism of action is unknown
• 70-year-old woman with SLE and HA previously treated with CTX, AZA, and
long-term GC; developed vertigo and ataxia after 4 infusions of RTX
– MRI had multiple brain lesions and biopsy showed PML
– The patient died 1 year later
• 45-year-old woman with SLE since 1982, previously treated with CTX, IV
methylprednisolone, and daily GC. CD4 count was low (<200). The patient
received 3 courses of RTX with daily GC in 2003–2006
– In April 2006, she developed neurologic symptoms and signs and had multiple
brain lesions by MRI, and was found to have JC virus in the CSF
– The patient died in July 2006
AZA, azathioprine; CSF, cerebrospinal fluid; GC, glucocorticoids; HA, hemolytic anemia;
MRI, magnetic resonance imaging.
US Food and Drug Administration. FDA Alert: rituximab (marketed as Rituxan). December 2006. Available at:
http://www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.pdf. Accessed December 18, 2007.
74
PML and RTX
• PML has not been diagnosed in any patient to
date in clinical trials
• Systematic reviews of PML and of rheumatic
disease and PML have suggested that patients
with SLE may have a unique susceptibility to
PML1
• Rheumatologists should familiarize themselves
with PML and consider it in the differential
diagnosis of immunosuppressed patients with
unexplained neurologic disease
1. Calabrese LH et al. Arthritis Rheum. 2007;56:2116-2128.
75
Immunocompetence and
Biologic Therapies:
Promises and Problems
• Efforts to improve our assessment of
compromised immune responses in patients
with rheumatic disease treated with biologics
include:
– Uniform assessment of infections (bacterial,
opportunistic, and viral) across trials and databases
– Uniform assessment of vaccine response from early
clinical trials
– Detailed assessment of in vitro immunity, including
cellular humoral and innate responses
76
The Use of B-cell–
Directed Therapies in SLE,
Vasculitis, and Other
Autoimmune Diseases
SLE, systemic lupus erythematosus.
77
Learning Objectives
• Describe the rationale of B-cell depletion for the
management of SLE, vasculitis, and other
autoimmune diseases
• Summarize recent clinical trial data on the use of
rituximab, belimumab, and epratuzumab in the
treatment of SLE
• Summarize recent clinical trial data on the use of
B-cell targeting in the treatment of Sjögren’s
syndrome
• Summarize recent clinical trial data on the
use of B-cell targeting in other vasculitides
78
B-Cell–Depletion Therapy
in SLE
• B lymphocytes may play a central role in the
pathogenesis of SLE
– As precursors of antibody-secreting cells, B cells are
the source of pathogenic autoantibodies
– B cells are not merely the passive producers of
immunoglobulins, but also play a central role in
autoimmunity
• B-cell depletion has recently emerged as a
promising therapeutic approach to the treatment
of autoimmune diseases, including SLE
79
RTX B-Cell–Depletion Therapy in
Patients With SLE: Long-Term
Follow-Up and Predictors of Response
• Observations of nonrandomized clinical experience (since June 2000)
in 41 patients with refractory SLE at University College, London1-3
– Mean duration of follow-up 37 months (2 patients lost to follow-up)
– Patients must have failed to respond to CTX or methotrexate
– RTX 1 g IV  2 (14 days apart) + CTX
• RTX therapy showed efficacy
– Mean duration of B-cell depletion was 4 months (range 2–15)
– Serum immunoglobulins decreased but not below lower limit of normal
– Anti-dsDNA antibody levels significantly reduced 6 months after B-cell–
depletion therapy
– Protein/creatinine ratio fell (but change did not reach statistical
significance)
• 13 patients re-treated
CTX, cyclophosphamide; dsDNA, double-stranded DNA; IV, intravenous; RTX, rituximab.
1. Edwards JC et al. N Engl J Med. 2004;350:2572-2581.
2. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020].
3. Ng KP et al. Ann Rheum Dis. 2006;65:942-945.
80
RTX B-Cell–Depletion Therapy in
Patients With SLE: Long-Term
Follow-Up and Predictors of Response
• 11 (55%) of 20 patients who flared did so 6–12 months
after treatment
• Predictors of lack of response
– Patients with anti-ENA antibodies (anti-Sm or anti-La) were
more likely to flare
– Lower serum C3 at baseline was associated with shorter time
to flare following B-cell–depletion therapy
• 2 (5%) of 39 patients in the cohort have died (varicella
pneumonitis and SLE pancarditis)
• AEs: single cases of hematuria, self-limiting neutropenia,
pneumococcal sepsis/pneumonia, serum sickness–like
reaction, active pancreatitis, seizure
AE, adverse event; ENA, extractable nuclear antigen.
1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020].
2. Ng KP et al. Ann Rheum Dis. 2006;65:942-945.
81
SLE: Case Series of RTX (anti-CD20)
Treatment of Patients With SLE
Refractory to Conventional Therapy
• Among 22 patients, RTX treatment1:
– Resolved anemia, thrombocytopenia, and/or cryoglobulinemia in all 18 patients with severe
hematologic manifestations
– Decreased daily proteinuria by ≥50% at 6 months in 4 (66%) of 6 patients with lupus nephritis
• Among 19 patients, RTX treatment2:
– Improved thrombocytopenia in 7 (64%) of 11 patients within 3 months, resolved anemia in 3
(75%) of 4 patients, and improved cutaneous manifestations of lupus in 4 of 4 patients
– Decreased levels of antiplatelet and anti-RBC antibodies, but not of anti-dsDNA antibodies
• Among 16 patients, RTX treatment3:
– Improved disease activity ( BILAG score) in 9 (56%) of 16 patients
– Did not prevent progression to stage 5 CKD in 5 patients with severe proliferative, crescentic
lupus nephritis
• Although some manifestations of refractory SLE may improve, some forms of lupus
nephritis may progress despite RTX therapy
CKD, chronic kidney disease; RBC, red blood cell.
1. Amoura Z et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124].
2. Lindholm C et al. Ann Rheum Dis. 2008;67(suppl 2):344 [abstract FRI0184].
3. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441].
83
RTX + IV CTX Induction for
Patients With Lupus Nephritis
• RTX + IV CTX may serve as an alternative induction regimen for patients with severe
lupus nephritis1
– 18 patients with biopsy-proven lupus nephritis (10 proliferative GN, 7 membranous GN, 1
unknown)
– RTX 375 mg/m2 IV weekly  4 + IV CTX (at weeks 1 and 4)
– After 6 months, 17 (94%) of 18 patients had clinical improvement; 1 had early relapse
•
Histologic examination showed significant improvement in most patients at 6 months
– At 2 years (n = 17), 15 (88%) of 17 patients had persistent clinical improvement; 2 had relapsed
• MMF may serve as a maintenance regimen for patients with severe lupus nephritis,
following RTX + IV CTX induction regimen2
– 35 patients with SLE and biopsy-confirmed active nephritis (ISN/RPS class IV [70%] or V
[30%]), refractory to standard treatment
•
•
Treated with RTX 750 mg IV + methylprednisolone 500 mg IV + CTX IV on days 1 and 15
Followed by maintenance MMF 1–2 g/d for 2 years
– At end of 2 years, significant improvement in C3, C4, anti-dsDNA antibodies, and proteinuria in
all patients; serum creatinine remained stable
– No SAE; 6 patients had mild viral infections
• No comparison with induction regimens using methylprednisolone+ CTX alone or
RTX alone
ISN, International Society of Nephrology; MMF, mycophenolate mofetil;
RPS, Renal Pathology Society; SAE, serious adverse event.
1. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021].
2. Guzman RA et al. Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260].
84
EXPLORER: Efficacy and Safety
of RTX in Patients With Moderate
to Severe SLE
• Phase II/III randomized, double-blind, placebo-controlled study to
evaluate efficacy and safety of RTX in patients (n = 257) with moderate
to severe SLE receiving background prednisone therapy
• Primary end point: Proportion of patients who achieved either a major
clinical response or partial clinical response measured by the BILAG
index at 52 weeks
• Secondary end points: Time-adjusted AUC of BILAG disease activity,
improvement in BILAG disease activity, time to flare, QOL, and
proportion taking <10 mg prednisone daily
• Study did not meet its primary end point or any of its six secondary
endpoints
• Reasons for failure unclear
• Clinical trial in lupus nephritis ongoing
AUC, area under the curve; EXPLORER, A Study to Evaluate the Efficacy and Safety of Rituximab in
Patients With Moderate to Severe Systemic Lupus Erythematosus; QOL, quality of life.
http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11247;
http://clinicaltrials.gov/ct2/show/NCT00137969; http://clinicaltrials.gov/ct2/show/NCT00282347
85
RTX B-Cell–Depletion Therapy in
Patients With SLE: Summary
• Observations of nonrandomized clinical experience in patients with
refractory SLE at 7 institutions suggests therapeutic efficacy of RTX when
used in addition to standard (anchor) therapy1-8
– Serum immunoglobulin and anti-dsDNA antibody levels decreased for at least 6
months after treatment1,2
– Presence of anti-Sm or anti-La antibodies or low C3 at baseline may identify patients
who will flare after treatment1,2
• However, a prospective randomized, double-blind, placebo-controlled
study of RTX in patients with moderate to severe SLE receiving
background prednisone therapy failed to demonstrate efficacy9
• 23 (64%) of 36 reported cases of PML in patients with rheumatic
diseases have occurred in patients with SLE, most of whom had not
received RTX10
PML, progressive multifocal leukoencephalopathy.
1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020]; 2. Ng KP et al. Ann Rheum Dis.
2006;65:942-945. 3. Tanaka Y et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0020]; 4. Amoura Z
et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124]; 5. Lindholm C, et al. Ann Rheum Dis
2008;67(suppl 2):344; 6. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441];
7. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021]; 8. Guzman RA, et al.
Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260]; 9. http://www.gene.com/gene/news/pressreleases/display.do?method=detail&id=11247; 10. Calabrese LH et al. Arthritis Rheum. 2007;56:2116-2128.
86
Phase II RCT of Belimumab in SLE:
Combined Response Rate Is Significantly
Higher for Belimumab-Treated Patients
• 1, 4, and 10 mg/kg belimumab dosed on days 0, 14, 28, and
then every week through week 52
• Changes in immunosuppressants, glucocorticoids permitted
• 46% combined response rate for patients with serologically
active disease receiving belimumab versus 29% for placebo
at week 521
• No dose response observed2
• 56% combined response rate for patients receiving
belimumab at week 762
In subjects with serologically active disease, significant improvements in SLE disease activity shown by SELENA-SLEDAI,
Physician’s Global Assessment and QOL (SF-36 PCS), and decreased BILAG 1A or 2B flares
RCT, randomized controlled trial; SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment;
SLEDAI, SLE Disease Activity Index; SF-36 PCS, physical component score of theSF-36 health survey.
1. Ginzler E et al. Ann Rheum Dis. 2007;66(suppl 2):56 [abstract OP0018].
2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017].
87
B-Cell Depletion With
Belimumab in Patients With SLE
• Efficacy1-3
– Although the primary study end point (a reduction in the SELENA-SLEDAI score)
was not achieved, there were indications of efficacy over 3 years:
• Combined response rate of 46% at week 52 (n = 235); increased to 65% with
belimumab treatment continued to week 160 (n = 170)
• Rate of SLE flares decreased progressively with belimumab treatment to 7% after 3 years
• Belimumab treatment allowed reduction of prednisone dose to 7.5 mg/d from
>7.5 mg/d at baseline in up to 44% of patients after 1 year and in up to 62% of
patients by 3 years
• Sustained response to belimumab is independent of type of autoantibody present
at baseline
• Safety4
– Belimumab is well tolerated in combination with antimalarials and
immunosuppressive drugs
– Similar incidence rates of AEs, SAEs, serious infections, and malignancies
between belimumab- and placebo-treated patients during the first year of treatment
– Incidence rate of AEs did not increase over time, during more than 3 years
of belimumab exposure
1. Petri M et al. Arthritis Rheum. 2007;56(9 suppl):S527 [abstract 1316].
2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017].
3. Ginzler E et al. Ann Rheum Dis. 2008;67(suppl 2):217 [abstract THU0253].
4. Merrill JT et al. Ann Rheum Dis 2008;67 (suppl 2):217 [abstract THU0254].
88
B-Cell Depletion With
Belimumab in Patients With SLE
• Biomarkers
– Changes correlated with clinical improvement
observed over 2.5 years of belimumab treatment:
•  in C3 and C4 levels
•  in anti-dsDNA antibody levels
•  in IgG, IgM, and IgE levels (more in subjects with elevated
levels at baseline)
• Reversion of anti-Sm and anti-RNP serologic findings from
positive to negative in some belimumab-treated subjects
Stohl W et al. Arthritis Rheum. 2007;56(9 suppl):S210 [abstract 426].
89
B-Cell Depletion With
Epratuzumab in SLE: RCTs
• 90 patients with SLE and moderate to severe flares
randomized in 2 phase II RCTs, each of which was
terminated prematurely because of interruptions in
medication supply
• Up to 4 treatment cycles over a 48-week period
– Placebo
– Epratuzumab 360 mg/m2
– Epratuzumab 720 mg/m2
• Primary end point: Reduction of all BILAG A to B, BILAG
B to C, no worsening in other systems, no addition or
increase in immunosuppressives/antimalarials or
corticosteroids above tapering levels
Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016].
90
B-Cell Depletion With Epratuzumab
in Patients With SLE
50
45
40
% of Patients
• Patients in both epratuzumab groups had
greater reductions in total BILAG scores
from weeks 4 through 48, compared with
placebo1
• Physician and patient global
assessment scores were also
significantly improved in the
epratuzumab-treated groups1
• Overall efficacy was most consistent
in the epratuzumab 360-mg/m2 group1
• Epratuzumab-treated patients used less
corticosteroid than placebo-treated patients
over 24 weeks2
• AE incidence was similar among
epratuzumab- and placebo-treated patients2
• Low incidence of immunogenicity (HAHA)2
35
30
25
20
15
10
HAHA, human antihuman antibody; ITT, intention to treat.
1. Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016].
2. Wallace D et al. Ann Rheum Dis. 2008;67(suppl 2):212 [abstract THU0238].
5
0
BILAG Response (ITT)
Placebo (n = 30)
Epratuzumab 360 mg/m2 (n = 34)
Epratuzumab 720 mg/m2 (n = 10)
91
B-Cell–Depletion Therapy in
Patients With SLE: Summary
• To date, no B-cell–directed therapy is approved
for the treatment of SLE
• Most clinical trials of both B-cell depletion and
anti-BAFF therapy, thus far, have been of either
inadequate design (open-label and uncontrolled)
or flawed by interruptions in medication supply,
making it difficult to determine the functionality of
these therapies in this setting
• Safety signals in controlled clinical trials to date
are modest, but caution clearly is indicated until
better safety and efficacy data are available
92
B-Cell Targeting in Sjögren’s
Syndrome (SS)
• Epithelial inflammatory
disease driven by cellular
and humoral factors
• No evidence of effective
remittive therapy
• Strong evidence of
– B-cell hyperactivity
– Polyclonal B-cell activation
– Hypergammaglobulinemia
– Multiple autoantibodies:
SSA/SSB, antifodrin, others
Micrograph courtesy of Leonard Calabrese, DO
– Elevated levels of BAFF
Ramos-Casals M et al. Ann Rheum Dis. 2005;64:347-354.
93
RTX for Primary SS
• Open trial in 12 patients with SS and 1 or more severe
disease manifestations (fatigue, parotid enlargement,
neuropathy, interstitial pulmonary disease [IPD], purpura)
treated with 1 g RTX, 100 mg methylprednisolone  2
• 10/10 fatigue; 3 parotid, 4 neuropathy, 1 IPD, 1 purpura
• Significant decrease in physician and patient global
assessment, fatigue, and joint pain; no significant change
for sicca assessments; no serum sickness or SAE related
to drug
• All patients became B-lymphopenic; reconstitution was
similar to that seen in studies of RTX in RA and SLE, with
transitional and plasmablastic phenotype and a paucity of
memory (CD27) B cells
• Larger placebo-controlled trials are needed
1. St. Clair EW et al. Arthritis Rheum. 2007;56: (suppl 9):S449-450 [abstract 1102].
2. Levesque MC et al. Arthritis Rheum. 2007;56: (suppl 9):S445-S446 [abstract 1091].
95
Safety and Efficacy of RTX in
SS: First Randomized
Placebo-Controlled Trial
• Primary SS causes significant symptoms but has
no effective therapy
• Subjects: Primary SS by EU-USA criteria,
antibodies to Ro and La, and fatigue >50% on
VAS
• Treatment: RTX 1 g  2 with prednisone
(tapering 60→30→0 over 14 days) or placebo
• Primary end point: ≥20% improvement in fatigue
EU, European Union; USA, United States of America; VAS, visual analog scale.
Dass S et al. Arthritis Rheum 2007;56:(suppl):S446-S447 [abstract 1094].
96
Safety and Efficacy of RTX in
SS: Results of the First
Double-blind Randomized
Placebo-Controlled Trial
• 18 available for analysis
– Failure to reach primary end point for fatigue (VAS)
– VAS fatigue improved 48% RTX vs 20% placebo
(NS); 8/9 versus 5/9 achieved ≥20% improvement in
fatigue VAS (NS); significant improvement in SF-36
– RTX patients had significant reductions in rheumatoid
factor (RF) but not Ro, La, or IgG
– 3 SAEs with 1 serum sickness
• Marked variability of clinical responses
Dass S et al. Arthritis Rheum. 2007;56:(9 suppl):S446 [abstract 1094].
97
Vasculitis and B-Cell
Targeting: Rationale
Cryoglobulinemia-Mediated Vasculitis
ANCA-Associated Vasculitis
• Sansonno D et al. Blood. 2003;101:3818-3826.
• Zaja F et al. Blood. 2003;101:3827-3834.
• Multiple case reports and small series: Lamprecht P
et al. Ann Rheum Dis. 2003;62:1230-1233; Cai FZ.
J Rheumatol. 2006;33:1197-1198; Basse G et al.
Transplantation. 2005;80:1560-1564; Quartuccio L
et al. Rheumatology (Oxford). 2006;45:842-846.
• Kay J et al. N Engl J Med. 2005;353:1605-1613.
• Keogh KA et al. Am J Respir Crit Care Med. 2006;173:180-187.
• Smith KG et al. Arthritis Rheum. 2006;54:2970-2982.
• Golbin JM et al. Arthritis Rheum. 2006;54(9 suppl):S527
[abstract 1265].
• Aries PM et al. Ann Rheum Dis. 2006;65:853-858; Flossmann O
et al. Ann Rheum Dis. 2006;65:841-844.
• Golbin JM et al. Clin Exp Rheumatol. 2007;25(1 suppl 44):
S74-S76.
• Brihaye B et al. Clin Exp Rheumatol. 2007;25
(1 suppl 44):S23-S27.
ANCA, antineutrophil cytoplasmic antibody.
1. Ruddy S et al, eds. Kelley’s Textbook of Rheumatology. 6th ed. Philadelphia, Pa: W.B. Saunders; 2001.
2. Vassilopoulos D et al. AIDS. 2005;19(suppl 3):S123-S127.
98
Repeated B-Cell Depletion
in ANCA-Associated Vasculitis
• 2006: Golbin et al suggested repeated treatment with
RTX and profound B-cell depletion are well tolerated in
relapsing WG; B-cell depletion appears effective for
maintaining remission and relapse was not seen in the
absence of B cells or ANCA
• 2007: Molloy et al retrospectively reported 4 patients
with refractory ANCA disease each responding initially
to RTX therapy; all patients eventually relapsed
despite ongoing B-cell depletion
• Until controlled studies are completed, the decision to
use RTX therapy in ANCA-associated disease should
be based on assessment of risk/benefit to the
individual patient.
WG, Wegener’s granulomatosis.
1. Golbin JM et al. Arthritis Rheum. 2006;54(suppl 9):S527 [abstract 1265].
2. Molloy E et al. Arthritis Rheum. 2007;56(suppl 9):S769 [abstract 2020].
99
RTX in ANCA-Associated
Vasculitis: Summary to Date
• In ANCA-associated vasculitis, most but not all
preliminary (noncontrolled) studies of B-cell depletion
suggest that this strategy is a safe and effective
mechanism-based approach for remission induction and
maintenance
• Repeated courses are equally effective and thus far
associated with few infectious complications
• Limited trials in cryoglobulinemia with and without HCV
infection have demonstrated efficacy and reasonable
safety of anti-CD20 based therapy
• A large controlled trial of RTX for ANCA-associated
vasculitis (RAVE) is fully recruited and analysis is
pending (www.clinicaltrials.gov)
HCV, hepatitis C virus.
101