aspectos patogénicos y terapéuticos de los linfocitos b. presente y futuro division of clinical...

Aspectos patogAspectos patogéénicos y nicos y terapterapééuticos de los linfocitos B. uticos de los linfocitos B.

Presente y futuro Presente y futuro

Division of Clinical Immunology & Rheumatology.

Autoimmunity Center of Excellence

Iñaki Sanz Paz

What do these diseases have in What do these diseases have in common?common?

Rheumatoid ArthritisRheumatoid ArthritisSystemic Lupus ErythematosusSystemic Lupus Erythematosus

ANCA-associated vasculitisANCA-associated vasculitis

Type 1 DiabetesType 1 Diabetes

Multiple SclerosisMultiple Sclerosis

Thrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic PurpuraBullous Pemphigoid Bullous Pemphigoid

Sjogren’s syndromeSjogren’s syndrome

DermatomyositisDermatomyositis

Opsoclonus-myoclonus syndromeOpsoclonus-myoclonus syndrome

Primary Billiary CirrhosisPrimary Billiary CirrhosisInflammatory Bowel DiseaseInflammatory Bowel Disease

Pemphigus vulgaris Pemphigus vulgaris

What do these What do these diseases have in diseases have in

common?common?

Autoimmune etiology

Autoantibodies (most)

Good therapeutic response to B cell depletion therapy (BCDT)


Rheumatoid ArthritisRheumatoid ArthritisSystemic Lupus Erythematosus

ANCA+ vasculitisANCA+ vasculitis



Autoimmune blistering diseases

Sjogren’s syndrome

Dermatomyositis

Primary Billiary Cirrhosis

B cell-mediated T cell-mediated

OverviewOverview

• Review the status of B cell depletion therapy (Rituximab)

• How extensive is its use now and in the future?

• Why and how are B cells important in disease

• Concerns about chronic B cell depletion

• B cells are important in maintaining health

• Can we afford to deplete them chronically?

• What remains to be learned?

Response of SLE to BCDTResponse of SLE to BCDT African-American female (24-year old) with chronic

history of autoimmune hemolytic anemia refractory to conventional therapy with high-dose glucocorticoids and cyclophosphamide.

After 3 years of follow-up she developed arthritis, rash, elevated anti-ds DNA antibodies and depressed serum complement levels.

The patient was treated with IV Rituximab (4 doses of 375 mg/m2 one week apart) as part of a phase I/II clinical trial

Course of SLE in Subject #14

Anti-dsDNAC3%SLAM

0

100

200

300

400

500

600

700

0 20 40 60 80Months0

20

40

60

80

100

120

140Rituximab

Looney, Anolik, Sanz. Arthritis and Rheum 50:2580, 2004

Response of SLE to Response of SLE to BCDTBCDT

• 45 year-old male with SLE for 10 years recently diagnosed 45 year-old male with SLE for 10 years recently diagnosed with class IV nephritis together with membranous features. with class IV nephritis together with membranous features.

• Clinically stable on Prednisone (15 mg/d) and Azathioprine Clinically stable on Prednisone (15 mg/d) and Azathioprine (2 mg/kg/d). (2 mg/kg/d).

• Treated with low-dose Rituximab (single dose of 100 mg/mTreated with low-dose Rituximab (single dose of 100 mg/m22) ) with good peripheral B-cell depletion (< 5/with good peripheral B-cell depletion (< 5/l). l).

• SLAM index decreased from 11 at baseline to 4 and 2 at 3 SLAM index decreased from 11 at baseline to 4 and 2 at 3 and 12 months respectively. and 12 months respectively.

• Anti-ds DNA antibodies decreased by 84% over 12 months. Anti-ds DNA antibodies decreased by 84% over 12 months.

• One year after Rx. a repeat kidney biopsy showed almost One year after Rx. a repeat kidney biopsy showed almost complete resolution of proliferative changes. complete resolution of proliferative changes.

• The patient remains on complete clinical remission 7 years The patient remains on complete clinical remission 7 years after treatment with Rituximab on no drugs except for after treatment with Rituximab on no drugs except for Plaquenil.Plaquenil.

Case presentationCase presentation

Post-Rituximab (1y)Pre-Rituximab

Response of SLE to Response of SLE to BCDTBCDT

Activity index: 12Proteinuria (24 h): 1.2 g

Activity index: 1Proteinuria (24 h): 0.13 g

• Clinical course: complete remission sustained 7 years after Clinical course: complete remission sustained 7 years after treatment in the absence of additional therapy treatment in the absence of additional therapy• ANA ANA

3/12/2005 3/26/2005 4/9/2005 2/23/2007

B cell depletion in refractory B cell depletion in refractory Thrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic Purpura

Anti-CD20 and/or Rituximab articles in the English literatureAnti-CD20 and/or Rituximab articles in the English literature

Blinded, Blinded, placebo placebo

controlled controlled (<10)(<10)

0

100

200

300

400

500

600

700

800

900

1994 1997

1998 2001

2002 2004 200620052003 2007

5 203 2971

B cell depletion with anti-CD20 B cell depletion with anti-CD20 monoclonal antibodies (Rituximab)monoclonal antibodies (Rituximab)

FDA approved for the treatment of non-Hodgkin follicular lymphoma (1997)

FDA approved for the treatment of Rheumatoid Arthritis refractory to anti-TNF agents (2006)

Impressive initial results in multiple autoimmune diseases:

• SLE, ITP, acquired factor VIII inhibitors, IgM-associated polyneuropathy, Sjogren’s….

• ANCA-associated vasculitis (Wegener’s)

• Multiple sclerosis

Rituximab targets CD20 specifically Rituximab targets CD20 specifically expressed on the surface of B-cellsexpressed on the surface of B-cells

Mouse

HumanHumanIgG1IgG1

Markers of B-Cell MaturationMarkers of B-Cell Maturation

Stem Pro-B Pre-B Immature Transitional Activated Memory Plasma Cell

Reprinted from Silverman G. Arthritis Rheum. 2006. 54:2356-2367.

MHC II

CD19

CD20

CD22

CD27

CD38

CD39

CD138

Rituximab targets. Plasma cells are Rituximab targets. Plasma cells are sparedspared

Pro-B Pre-B

Immature

Transitional

Naïve

Memory

Plasma Cell (long-lived)

Plasmablast (short-lived)

CD20CD20

RituximabRituximab

Protective vs pathogenic antibodies

Anti-microbial

Anti-ds DNA

Anti-RBP antibodies (Ro, La, Sm/RNP)

Anti-CD20: Mechanism of ActionAnti-CD20: Mechanism of Action

Antibody-Dependent Antibody-Dependent Cell-Mediated Cell-Mediated Cytotoxicity (ADCC)Cytotoxicity (ADCC)

Complement-dependentComplement-dependentCytotoxicityCytotoxicityComplement-dependentComplement-dependentCytotoxicityCytotoxicity

FcFcRIIIRIIIAA

CD20CD20

CD2CD200 MACMAC

ApoptosisApoptosisApoptosisApoptosis

B B cellcell

Anti-CD20 Anti-CD20 antibodyantibody

Macrophage, monocyte, NK cell

Rituximab in non-Hodgkin’s Rituximab in non-Hodgkin’s LymphomaLymphoma

• FDA-approved in 1997 (refractory, low-grade FL)

• Close to 1.0 million patients treated

• Monotherapy: 50% response

10% complete remission

• RTX + chemotherapy: 81-97% response 35-74%

complete remission

• Almost complete peripheral B-cell depletion ≥ 6 months

• Stable levels of total serum immunoglobulins

• Good safety profile without significant increase in infectious complications

Infusion-related reactions in multicenter trial (N=166)Infusion-related reactions in multicenter trial (N=166)1,21,2

1 McLaughlin P, et al. J Clin Oncol.

Num

ber

of

pati

en

ts

1st

infusion2d

infusion3rd

infusion4th

infusion

Grade 1Grade 2Grade 3/4 12% (3)

3% (4)

2 NCI Common Terminology Criteria for Adverse Events v3.0

Pre-Dose#2

Pre-Dose#4

3 MOPost-Rx

6 MOPost-Rx

9 MOPost-Rx

12 MOPost-Rx

Media

n a

bso

lute

CD

19

count

in p

eri

phera

l blo

od (

cells

/l)

Peripheral B-cell depletion Peripheral B-cell depletion in lymphoma patients (pivotal trial)in lymphoma patients (pivotal trial)

McLaughlin P, et al. J Clin Oncol. 1998;16:2825-2833.

Fleischmann R et al. Arthritis Rheum. 2006;54(9 suppl):S238 [abstract 483].

Rituximab 2 x 500 mg + MTX

Phase IIOpen -label extension study of rituximab treatment

Course of rituximab Course of rituximab

Phase IIa

Placebo

Rituximab 2 x 1000 mg

Phase IIb DANCER

Placebo


Long-term follow-up

-



+ MTX


+ MTX

Rituximab 2 x 1000 mg +

cyclophosphamide

Phase III REFLEX

Placebo



Phase 2/3Open-label extension study of rituximab treatment

Phase 2a

Placebo


Phase 2b DANCER

Placebo


Long-termFollow-up

–




+ MTX


cyclophosphamide

Phase 3 REFLEX

Placebo


All patients in the OL extension studyreceived MTX 10–25 mg/wk plus methylprednisolone 100 mg IV X 2 and570 mg oral between infusions

Timing of the 2nd course depended on MD discretion

Studies of Rituximab in RAStudies of Rituximab in RA

REFLEX Trial: Change inRadiographic End Points at Week 56

2.31

0.99

1.32

1

0.410.59

0.0

0.5

1.0

1.5

2.0

2.5

Total Genant-Modified Sharp

Score

Joint SpaceNarrowing

Erosion Score

Placebo + MTX (n = 184) RTX + MTX (n = 273)

Mean

Ch

an

ge

Primary analysis: radiographs within time window, linear extrapolation from Week 24 for missing values.

Keystone EC et al. Ann Rheum Dis. 2006;65(suppl 2):58 [abstract OP0016].

P = 0.0043

P = 0.0007

P = 0.0106

Mean serum IgG (up to wk 56)

Lower normal limit

0

2

4

6

8

10

12

14

16

-5 5 15 25 35 45 55

Time (Weeks)

Me

an

Ig

G (

ng

/mL

)

MTX R R+CTX R+MTX

Mean IgM (up to week 56)

0

0.5

1

1.5

2

2.5

-5 5 15 25 35 45 55

Time (Weeks)

Me

an

Ig

M (

ng

/mL

)

MTX R R+CTX R+MTX

Lower normal limit

Changes in total RF (median)

-160

-140

-120

-100

-80

-60

-40

-20

0

20

0 10 20 30 40 50

Time (Weeks)

Med

ian

Ch

an

ge (

IU/L

)

MTX R R+CTX R+MTX

Rituximab targets. Plasma cells are Rituximab targets. Plasma cells are sparedspared

Pro-B Pre-B

Immature

Transitional

Naïve

Memory

Plasma Cell (long-lived)

Plasmablast (short-lived)

CD20CD20

RituximabRituximab

Protective vs pathogenic antibodies

Anti-microbial

Anti-ds DNA

Anti-RBP antibodies (Ro, La, Sm/RNP)RF/anti-CCP

antibodies

Adverse effects of Rituximab in RA patientsAdverse effects of Rituximab in RA patients

MTX(n=40)

Rituximab(n=40)

Rituximab/CTX(n=41)

Rituximab/MTX(n=40)

All Events 145 (85%) 169 (88%) 161 (85%) 138 (85%)

RA exacerbation 55% 40% 37% 18%

Hypotension 18% 30% 29% 18%

Hypertension 15% 18% 7% 25%

Nasopharyngitis 15% 10% 7% 15%

Arthralgia 8% 8% 5% 13%

Back pain 8% 13% 7% 3%

Hyperglycaemia 10% 5% 7% 8%

Cough- 15% 5% 8%

Flushing 8% 13% 5% 3%

Headache 5% 5% 7% 8%

Infections: Most Frequently Reported(up to week 48)

MTX

(n=40)

Rituximab

(n=40)

Rituximab + CTX(n=41)

Rituximab + MTX (n=40)

Infections 24 (33%) 14 (30%) 16 (29%) 24 (33%)

-

Herpes simplex 5% 3% 5% 3% Herpes zoster 5% - 2% 5% URTI viral 3% - 2% 5% UTI 5% 3% 2% -

Bronchitis (bacterial) 5% - 2% - Pharyngitis (viral) 3% 3% - 3%

-UTI (bacterial) 5% 3%

Summary for RASummary for RA A single course of rituximab added to existing MTX

produced significant and sustained improvement in patients

with severe, seropositive, active rheumatoid arthritis.

Significant improvement in clinical outcomes was

achieved at week 24 and was maintained out to at least 48

weeks without further treatment.

Treatment with rituximab was well tolerated, with a

favorable safety profile being observed over 48 weeks

follow-up.

Decrease in disease-associated autoantibodies but not on

total Ig levels or protective anti-microbial antibodies

Recommendations for RARecommendations for RA

Indicated for active RA with resistance or toxicity to anti-TNF

drugs

Combination with MTX

Administered as two IV infusions of 1,000 mg two weeks

apart

Pre-medication with glucocorticoids and anti-histamines

recommended

Re-treatment possible (safe and effective) after 6 months

Indications and recommendationsIndications and recommendations

•FDA approved for the treatment of follicular non-Hodgkin lymphoma

•FDA approved for the treatment of Rheumatoid Arthritis refractory or

unable to use anti-TNF

•Other autoimmune diseases when conventional therapy fails or has

unacceptable toxicity:

• Kidney transplant:

• treatment of humoral rejection

• tolerance induction in HLA-sensitized recipients

• Future indications or applications:

•Pulmonary diseases: Asthma, COPD?

•Adjuvant therapy in some malignancies?

Rituximab: adverse effects and other safety consideraionsRituximab: adverse effects and other safety consideraions

1. Infusion reactions:1. Frequent in lymphoma and SLE2. Rare in other diseases including RA3. Usually mild (NCI grade 1-2), mostly with first infusion4. May be due to lymphocyte (tumor) lysis or serum sickness-like

disease due to HACA2. Infections

1. Not increased2. Usually common and mild infections3. However, fulminant hepatitis B reactivation and PML have been

reported3. Hypo-gammaglobulinemia: rare may require IVIG replacement4. Late-onset neutropenia: uncommon (10%), transient, responds to GM-

CSF, may preclude further treatment

Why – how are B cells involved Why – how are B cells involved

in in

many different conditions?many different conditions?

Ectopic GCs in RA synovium

CD8+IFN+

CD8+IFN-

Kang YM, Zhang X, Wagner UG, Yang H, Beckenbaugh RD, Kurtin PJ, Goronzy JJ, Weyand CM.

J Exp Med. 2002 May

http://www.jem.org/content/vol195/issue10/images/large/011565f4a.jpeg

http://www.jem.org/content/vol195/issue10/images/large/011565f4a.jpeg

Human Lupus NephritisHuman Lupus NephritisWith Infiltrating PlasmaWith Infiltrating PlasmaCells Cells

CD138 Human Lupus Human Lupus NephritisNephritisWith Germinal With Germinal CentersCenters

B-Cell Subsets and MicrostructuresB-Cell Subsets and Microstructuresin Lupus Nephritis in Lupus Nephritis

CD21

CD20

Courtesy of Dr. M. Clark, University of ChicagoCourtesy of Dr. M. Clark, University of Chicago

A B

Cortesia del Dr. J. Perez, Servicio de Nefrologia, Hospital General de Albacete

Renal B cell infiltrates in Churg-Strauss Syndrome

T Cell Activation in Rheumatoid Synovium is B Cell Dependent

S. Takemura, et al J.Immunol. 167: 4710-8, 2001

Interferon-

0

200

400

600

800

1000

1200

0 mcg 300 mcg 600 mcg

anti-CD20 mAb/day

Ectopic neolymphogenesis. Role of B Ectopic neolymphogenesis. Role of B cellscells

T

FDC

DC

LTßR

BLC (CXCL13)

LTαß B

ELCSLCBLC

BLC

LTßR

LTαß

ELCSLC

ChemokinesChemokines

ChemokinesChemokines

BLCStroma

B-cell functions

Formation and organization of peripheral lymphoid tissue

B cell follicles, germinal centers, T cell zone, marginal zoneB cell follicles, germinal centers, T cell zone, marginal zone

AntibodyAntibodyindependentindependent

Antigen presentation

Cytokine production

Chemokineproduction

B-cell (Auto)-antibody production(Auto)-antibody productionPlasma

cellAntibodyAntibodydependentdependent

LTα-dependent

LTα-independent

• T-cell activation (CD4 and CD8)T-cell activation (CD4 and CD8)• Th cell polarization (Th cell polarization ( Th Th22?)?)

• FFTHTH cell recruitment? (CXCL13-CXCR5) cell recruitment? (CXCL13-CXCR5)• Treg cell regulation: priming vs. suppressionTreg cell regulation: priming vs. suppression• Recruitment and regulation of DCs Recruitment and regulation of DCs • Anti-inflammatory actions (IL-10, TGFAnti-inflammatory actions (IL-10, TGF) ) • Pro-inflammatory actions (IL-6 + TGFPro-inflammatory actions (IL-6 + TGFββ): ): TH17?TH17?

Secondary tissue: protective or pathogenic responsesTertiary tissue: protective (BALT-influenza), pathogenic (BALT-RA/COPD)…….

Cytokine dependent effector Cytokine dependent effector functions of B cellsfunctions of B cells

Antibody

Regulation of T cell responses (APC function)

Lymphoid architecture(ectopic lymphoid tissue)

Cytokines/Chemokines

B cell

Courtesy of F. Lund (Trudeau Institute)

Multiple Roles for B Cells in RAMultiple Roles for B Cells in RA

Autoantibody productionAutoantibody production Cytokine secretionCytokine secretionAntigen presentationAntigen presentationT cell co-stimulationT cell co-stimulation

Antibody

APC function

Regulation of Th1/Th2 balance

Lymphoid architecture

B cellB cell

Generation of T cell memory

Cytokines/Chemokines

B cell effector functions

“New” “effector” and “regulatory” functions described for B cells, some of which are independent of antibody production



Rheumatoid ArthritisRheumatoid ArthritisSystemic Lupus Erythematosus

ANCA+ vasculitisANCA+ vasculitis



Autoimmune blistering diseases

Sjogren’s syndrome

Dermatomyositis

Primary Billiary Cirrhosis

B cell-mediated T cell-mediated

Functional Implications of Functional Implications of

TargetedTargeted

B cell DepletionB cell Depletion

What happens when you deplete B cells?

Will it be safe to chronically deplete B cells?

Janus quality of B cells

Treg primingTreg primingTreg inhibition

T cell activationT cell activation T cell anergy

Cancer surveillanceCancer surveillanceCancer progression

DC recruitment DC inhibition (IL-10)DC inhibition (IL-10)

Th1 cytokines (Be1) Th2 cytokines (Be2)Th2 cytokines (Be2)

Protective AbPathogenic AutoabPathogenic Autoab

Pro-inflammatory TNF, IFN, IL-12p40

Anti-inflammatory Anti-inflammatory IL-10, TGFIL-10, TGFββ

Vaccine protectionAutoimmunity

http://upload.wikimedia.org/wikipedia/en/f/f4/Janus-Vatican.JPG

Ab

solu

te B

cell

#

0.1

1.0

10.0

100.0

1000.0

0 2 12 36

Months

Group A (30%)•Overshoot of PBL B-cells•Eventual disappearance of autoantibodies •Complete, sustained clinical remission (up to 5 years)•Negative anti-RBP antibodies (Sm, Ro, La, U1RNP) at baseline

Group B (70%)Group B (70%)•Normal B-cells levels post BCDTNormal B-cells levels post BCDT•Autoantibodies persistAutoantibodies persist•Clinical relapse 3 months (mean) Clinical relapse 3 months (mean) after B-cell repopulationafter B-cell repopulation•Positive anti-RBP antibodies at Positive anti-RBP antibodies at baselinebaseline

Two types of response in SLE after BCDT

Group A is characterized by expansion of transitional B Group A is characterized by expansion of transitional B cells and greatly delayed memory B cell repopulationcells and greatly delayed memory B cell repopulation

CD38

SLE-group A

TT

NNMM

Neonate

NNMM

TT

Healthy adult

TT

NNMM

CD

24

SLE-group B Short-term

responder

MM

SLE post-Rituximab (32 mo)

N

T1

T2

M

T2

N

M

Normal control

T1

Rhodamine 123 Rhodamine 123

T3


- Vaccination and immunization status

- Poor responses to neo-antigens:

- Vaccination should preceed treatment

- Diminished responses to recall antigens:

- Will re-vaccination be necessary upon B cell replenishmnent?

- Will B cell memory responses come back upon repopulation?

- Will pre-existing T cell memory survive and maintain appropriate

quality (Th1 versus Th2)?

Clinical considerations for Chronic B cell depletionClinical considerations for Chronic B cell depletion

•When to re-treat?•How to monitor response?•Who to re-treat

•Safety recommendations:•Hepatitis B vaccination status – revaccinate before treatment•Pneumococcal vaccination•Surveillance for EBV/CMV reactivation?•Surveillance for Progressive Multifocal Leukoencephalopathy

•Clinical•Immunological: JC virus titers, JC-specific T cell responses

•Needed epidemiological and clinical studies•Mycobacterial and other opportunistic/chronic infections? •Cancer incidence•Progression of atherosclerosis•Development of second autoimmune disease?

•

A lot remains to be learnedA lot remains to be learned

• Final outcome will depend on the balance of B cell reconstitution

between different B cell populations

• Immature versus memory

• Autoimmune memory versus protective memory

• Pro-inflammatory versus anti-inflammatory cytokine

• Careful analysis of emerging populations may indicate:

• Prognosis’

• How and when to retreat

• Risk of infections

• Risk of disease relapse

"Some cause happiness "Some cause happiness wherever they go; others, wherever they go; others,

whenever they go." whenever they go."

Oscar Wilde

CD20CD3

T:B Aggregates in HumanLupus Nephritis

CD3 CD20

Summary• B cell depletion therapy has demonstrated efficacy and safety in NHL and RA• Efficacy has been suggested in open label/uncontrolled studies in multiple other autoimmune disease.• Preliminary efficay and safety has also been found in controlled, randomized studies • Safety profile has been favorable



Phase IIOpen -label extension study of rituximab treatment

Course of rituximab Course of rituximab

Phase IIa

Placebo


Phase IIb DANCER

Placebo


Long-term follow-up

-



+ MTX


+ MTX


cyclophosphamide

Phase III REFLEX

Placebo



Phase 2/3Open-label extension study of rituximab treatment

Phase 2a

Placebo


Phase 2b DANCER

Placebo


Long-termFollow-up

–




+ MTX


cyclophosphamide

Phase 3 REFLEX

Placebo


All patients in the OL extension studyreceived MTX 10–25 mg/wk plus methylprednisolone 100 mg IV X 2 and570 mg oral between infusions

Timing of the 2nd course depended on MD discretion

Study Schema of All Rituximab Retreatment Presentations

Rituximab Clinical Questions

2. Can a patient treated with rituximab be safely/effectively vaccinated?

Oren C et al. Arthritis Rheum. 2006;54(9 suppl):S515 [abstract 1234].

Response to Vaccination of RA Patients Treated with Rituximab

29 RA treated with DMARDs

• 8 RA treated with rituximab

• 21 healthy controls

Vaccinated with split virion inactivated vaccine (B/Shanghai, A/New Caledonian, A/California

Criterion for active response:

• > 4-fold rise in antibody titer or seroconversion

All patients increased in titers to New Caledonian

DMARD RA and healthy responded to A/California strain, rituximab-treated patients with RA did not respond to A/California strain

Rituximab may impair immune responses to vaccination

Immunization of Systemic Lupus Erythematosus Patients Treated With

Rituximab 12 patients in a Phase 1 trial were immunized 7 months after

rituximab treatment

Patients were assessed for a doubling of antipneumococcus and anti-TT antibody levels at Weeks 0 and 4

B-cell depletion was heterogeneous with those totally depleting (6) failing to respond to either vaccine and those with partial/short-lived depletion with variable responses (2 normal)

Conclusions:

B-cell depletion can impair responsiveness to bacterial vaccine challenge

Clinicians should be vigilant about recommended immunizations and consider vaccination before starting B-cell depletion therapy

Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323].


3. Which patients are appropriate for treatmentwith rituximab?

Can we predict who will respond to Rituximab?

Rituximab and Belimumab: Is RF or anti-CCP important?

Rituximab:

Patients who are seronegative for RF and/or anti-CCP respond less well to rituximab¹

0

10

20

30

40

50

60

70

PBO RTX PBO RTX

ACR20 ACR50 ACR70

RF + anti-CCP + RF – anti-CCP –

1Tak PP et al. Arthritis Rheum. 2006;54(9 suppl):S368 [abstract 833]. ²Huizinga TW et al. Arthritis Rheum. 2006;54(9 suppl):S368 [abstract 832].

(n = 107) (n = 157) (n = 16) (n = 29)

Anti-RNA binding protein autoantibodies are associated Anti-RNA binding protein autoantibodies are associated with poorer response to Rituximab in SLE (May Be with poorer response to Rituximab in SLE (May Be

Upstream Pathogenetic Factors for Type I Interferon)Upstream Pathogenetic Factors for Type I Interferon)

IgG-IgG-ENA ENA immunimmune e complecomplexx

PlasmacytoidPlasmacytoiddendritic celldendritic cell

(involves Fc(involves FcR)R)

IFN-IFN-MyeloidMyeloid

dendritic celldendritic cell

APRILAPRILBAFFBAFF

B cell survival factorsB cell survival factors

Banchereau J et al.Banchereau J et al. Immunity. Immunity. 2004;20:539-550. 2004;20:539-550.Litinskiy MB et al. Litinskiy MB et al. Nat Immunol.Nat Immunol. 2002;3:822-829. 2002;3:822-829.Jego G et al. Jego G et al. ImmunityImmunity. 2003;19:225-234.. 2003;19:225-234.

Plasma cellPlasma celldifferentiationdifferentiation

(with other factors e.g. IL-6)(with other factors e.g. IL-6)

Courtesy of Gregg Silverman. All rights reserved.Courtesy of Gregg Silverman. All rights reserved.

IL-6IL-6

B cell


4. Are there new radiographic data?

REFLEX Trial: Change inRadiographic End Points at Week 56

2.31

0.99

1.32

1

0.410.59

0.0

0.5

1.0

1.5

2.0

2.5

Total Genant-Modified Sharp

Score

Joint SpaceNarrowing

Erosion Score


Me

an

Ch

an

ge

Primary analysis: radiographs within time window, linear extrapolation from Week 24 for missing values.


P = 0.0043

P = 0.0007

P = 0.0106

REFLEX Trial: Change inRadiographic End Points at Week 56 Is Not Dependent on Clinical Response at

Week 24

2.39

0.93

1.46

0.93

0.44 0.49

0.0

0.5

1.0

1.5

2.0

2.5

Total Genant Score Joint SpaceNarrowing

Erosion Score


Subgroup analysis of patients who were ACR20 nonresponders at Week 24 was also conducted using imputation for all withdrawals/rescue patients prior to Week 24.


P = 0.0271

P = 0.0396

P = 0.0126

Mea

n C

han

ge

ACR20 nonresponders at Week 24

Janus properties of B cells

Treg primingTreg primingTreg inhibition

T cell activationT cell activation T cell anergy

Cancer surveillanceCancer surveillanceCancer progression

DC recruitment DC inhibition (IL-10)DC inhibition (IL-10)

Th1 cytokines (Be1) Th2 cytokines (Be2)Th2 cytokines (Be2)

Protective AbPathogenic AutoabPathogenic Autoab

Pro-inflammatory TNF, IFN, IL-12p40

Anti-inflammatory Anti-inflammatory IL-10, TGFIL-10, TGFββ

Vaccine protectionAutoimmunity

http://upload.wikimedia.org/wikipedia/en/f/f4/Janus-Vatican.JPG

•Outline•Introduction. Clinical Vignettes•Scope of BCDT•Anti-CD20, mechanisms•RA:

•Initial trial. Efficacy, safety•Re-treatment•Effect on bone erosions

•SLE•Trial•AE: HACA data•Clinical example•Immunology•Tolerance?

•Mechanisms of B cell depletion•Effects on T cells, lymphoid tissue

•Challenges:•Safety: PML•Vaccination•Th1 deviation•Janus effects

•Conclusions

Effector B cell subsets have distinct cytokine and transcriptional profiles

Con

trol

Be1 cells days 1-4

Be2 cells days 1-4


Harris et al. Nat Immunol 2001

Rituximab Therapy in Adults With Chronic Rituximab Therapy in Adults With Chronic ITPITP

• Twenty-five patients with chronic ITP• Treatment refractory (failed 2-5 Rxs)• Four weekly doses of rituximab 375 mg/m2

• Response criteria– Complete response (CR): platelets rise to normal counts

(ie, >100 109/L)– Partial response (PR): platelets rise to counts between 50

and 100 109/L– Minor response (MR): platelets rise to counts <50 109/L

with no need for continued treatment– No response or refractory disease: no rise in platelet

count or a rise 50 109/L, with a need for continued treatment

Stasi R et al. Blood. 2001;98:952–957.

Clinical Course of a Patient With Chronic Clinical Course of a Patient With Chronic ITP Responding to RituximabITP Responding to Rituximab

Stasi R et al Blood. 2001;98:952–957.

700

600

500

400

300

200

100

0

PDN

lv lg

VCR

Splemectomy

Cy

Rituximab

Pts

. X

10

9/L

05/95 06/95 08/9510/95 11/95 01/96 02/9604/96 05/96 10/98 12/98 03/99 04/99 05/9906/99 07/99 10/00

• Acetaminophen: 1 gram PO • Diphenhydramine: 50 mg PO • Methyl-prednisolone: 100 mg IV over 10 minutes• Rituximab: 1000 mg IV at 50mg/hr, 30 min after Solumedrol

• Rituxan infusion may be increased 12.5ml/hr (50mg/hr) every half hour to a max of 100ml/hr (400mg/hr) as long as patient is stable.

Guidelines for the administration of Rituximab

Two infusions of 1000 mg IV two weeks apart

HACAs (Human Anti-Chimeric Antibodies) HACAs (Human Anti-Chimeric Antibodies)

• Negative/low in most patients (11/17)

• High titer (>100 ng/mL) in 6/17 including 2 in high dose group

• Average peak for high titer = 4767 ng/mL

• Long term persistence

110

1001000

10000

0 4 8 12

Month

HA

CA

(ng/

ml)

Non-depleters

Depleters

High HACAs are associated with High HACAs are associated with poor B-cell depletion and active lupuspoor B-cell depletion and active lupus

0.1

1

10

0 3 6 9 12Month

% C

D19

+ l

ymp

ho

cyte

s

High HACA

No or Low HACA

SummarySummary Targeting of B cells can provide an effective alternative

to TNF inhibitors or T-cell–directed therapies for the treatment of autoimmune rheumatic diseases

RA patients retreated with rituximab had a successful therapeutic response with no increase safety issues or infections

Rituximab may impair clinical response to vaccination

• Physicians should be vigilant regarding vaccination during therapy

A host of B-cell targeting agents are now in development for the treatment of autoimmune diseases and organ rejection

• RA, SLE, Vasculitis, WG, SS, ITP, Diabetes, TTP, blistering diseases, myositis,

Atacicept(TACI-Ig)

Rituximab is a chimeric antibody consisting of both human and mouse regions

Other agents are fully humanized so the entire construct has human components

TRU-015 is a SMIP (small modular immunopharmaceutical) with a shortened light chain attached to the heavy chains

Decoy receptor agents fuse the ligand binding domains to human IgG Fc portion

Human (green)

Mouse (red)

Human (green)

Human (green)

Human (green)

Mouse (red)

Human (green) BR3-FC

Rituximab

TRU-015

OcrelizumabOfatumumabBelimumab

Construction of B-Cell Targeting AgentsConstruction of B-Cell Targeting Agents

SummarySummary

B cell depletion appears to be a safe and highly promising modality for the treatment of multiple autoimmune diseases.

Safety and efficacy appears to also extend to chronic or repeated B cell depletion achieved by repeated infusions of Rituximab

Clinically relevant hypoglobulinemia appears to be rare although IVIG replacement may be required (mostly in young children)

Serious infusion reactions are rare and occur mostly with the first infusion. However, HACA formation may occur mostly in patients with SLE leading to infusion reactions, faster Rituximab clearance and decreased efficacy.

SummarySummary Serious infectious are rare. However,

fulminant hepatitis B has been reported. Similarly, two cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in two SLE patients.

Immune responses to neo-antigen and recall responses to previous immunizations may be compromised.

Longer surveillance may be required to understand the consequences of prolonged B cell depletion


1. How effective/safe is retreatment?

2. When should patients be retreated?

3. Which patients are appropriate for rituximab treatment?Can we predict who will respond to rituximab?

4. Can a patient treated with rituximab be safely/effectively vaccinated?

5. How should we monitor patients (before and after Rx.)?


1. What’s the impact of B cell therapies on mycobacterial infections?

2. What’s the impact of B cell depletion on pre-established B and T cell memory for chronic viral infections

1. EBV, CMV

2. Hepatitis B virus

3. JC/BK polyoma virus (PML, kidney graft loss)

3. How is autoimmunity impacted: secondary autoimmunity?

4. Is cancer surveillance altered?

Platelet Response to Platelet Response to RituximabRituximab

Stasi R et al. Blood. 2001;98:952–957.

Weeks

600

500

400

300

200

100

01 2 3 4 5 6 7 8 9 10 11 12

CR (n=5)

PR (n=5)

NR (n=15)

Pre

Pts

. X

10

9/L

Rituximab Therapy in Children With Rituximab Therapy in Children With Refractory Autoimmune Hemolytic Refractory Autoimmune Hemolytic AnemiaAnemia

• Fifteen children, median age at diagnosis 2 years (range 0.3 to 14 years)

• All refractory to 2 courses of immunosuppressive therapy

• Two to 4 weekly doses of rituximab 375 mg/m2

• All pre-medicated with diphenhydramine and methylprednisolone

• After completing treatment, all children received 400 mg/kg IVIG every 3 weeks for 6 months

Zecca et al. Blood. 2003;101:3857–3861.

Zecca et al. Blood. 2003;101:3857–61.

Hgb and Absolute Reticulocyte Hgb and Absolute Reticulocyte CountsCounts

The difference between pretreatment and posttreatment values is statistically significant (P<.001)

Pretreatment 2 Months

800

700

600

500

400

300

200

100

0R

etic

ulo

cyte

s (x

109 /

L)

16

Pretreatment

14

12

10

8

6

4

2

0

2 Months

Hem

og

lob

in (

g/d

L)

Treatment of IgM Antibody-Treatment of IgM Antibody-associated Polyneuropathy With associated Polyneuropathy With RituximabRituximab

• Patients

– Twenty-one patients treated with 375 mg/m2 rituximab x 4

– Thirteen untreated controls

• Re-treatment of 16 patients with 375 mg/m2 rituximab x 2 then x 1 every 10 week

Pestronk A et al. J Neuro Neurosurg Psych. 2003; 74:485–489.

Pestronk A et al. J Neuro Neurosurg Psych. 2003;74:485–489.

Treatment With Rituximab Resulted Treatment With Rituximab Resulted in Improved Strengthin Improved Strength

Error bars= SEMP<.001

Treated Untreated

Dis

tal st

rength

(%

norm

al)

Baseline 1 Year 2 Years

Antibody Titers and Immunoglobulin levels in Antibody Titers and Immunoglobulin levels in Rituximab-treated PatientsRituximab-treated Patients

Pestronk A et al. J Neuro Neurosurg Psych. 2003;74:485–489.

020

4060

80100

120140

Untreated

IgM Anti-GM1 MAG

IgM Anti-tet IgG

Mea

n %

bas

elin

e (S

EM

)

1 Year 2 Year

IgM Anti-GM1 MAG

Caveats of Rituximab Therapy• Controlled clinical trials are needed to determine efficacy

• Combination therapy may be needed in certain patients and/or diseases

• Effects of rituximab on host defenses needs additional study

• Rituximab has been used safely in children as young as 3 months old. However, IV Ig in young children may be necessary

• Total IgG and IgG anti-tetanus antibodies appear to be unaffected even after 2 years of therapy with rituximab alone; however, significant reductions in total IgM do occur

• Antibody response to immunization may be blunted or even completely eliminated

• High level HACAs can be induced, at least in SLE.

REFLEX Trial: REFLEX Trial: Median CD19+ B-Lymphocyte Median CD19+ B-Lymphocyte

CountsCounts

0

50

100

150

200

250

300

350

400

450

500

0 4 8 12 16 20 24

Weeks

Med

ian

CD

19+

cou

nt (

cells

/uL)

Placebo + MTX (n = 209)Rituximab + MTX (n = 308)

Error bars represent the interquartile range.Cohen S et al. Arthritis Rheum. 2006;54:2793-2806.

0

20

40

60

80

100

120

0 10 20 30 40

Months

PR CR

Transient B-cell Depletion With Rituximab Resulted in Lasting Complete Response

Cooper N et al. Blood. 2002;100:Abstract:187.

Per

cen

t M

ain

tain

ing

Res

po

nse

Long Term Efficacy of Retreatment With Long Term Efficacy of Retreatment With Rituximab in DMARD Failures/TNF IRRituximab in DMARD Failures/TNF IR

Placebo patients eligible to receive their first course of rituximab within the extension study

Need for retreatment was determined by the treating physician• Only criterion for retreatment

was residual disease activity (defined as ≥ 8 SJC and TJC)

Completer analysis• 145 patients received C2• 99 reached Week 24 C2

0

10

20

30

40

50

60

70

80

C1 Week 24 C2 Week 24

ACR 20 ACR 50 ACR 70

C1, course 1; C2, course 2; SJC, swollen joint count; TJC, tender joint count.Emery P et al. Arthritis Rheum. 2006;54(9 suppl):S228 [abstract 458].

Long-Term Efficacy of Retreatment Long-Term Efficacy of Retreatment with Rituximab in anti-TNF Failureswith Rituximab in anti-TNF Failures

279 patients prior Rx with anti-TNF: had 2 courses of rituximab

155 reached wk 24 of 2nd course

Repeated courses not associated with increase in infections/overall incidence of adverse event (AE)

1669 pt-years of follow-up, one or multiple courses of rituximab showed no new safety signals

Patients maintained their HAQ-DI response and improved their

SF-36 with retreatment.²

65

33

12

66

33

12

72

42

21

56

31

16

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

79

13

6

79

13

6

88

25

13

81

25

13

0

10

20

30

40

50

60

70

80

90

100

Moder

ate/

Good

Low Dis

ease

Remis

sion

Mod

erat

e/G

ood

Low Dis

ease

Remis

sion

% P

atie

nts

Course 1

Course 2

¹Keystone E et al. Arthritis Rheum. 2006;54(9 suppl):S328 [abstract 725]. ²Tak PP et al. Arthritis Rheum. 2006;54(9 suppl):S403 [abstract 926].

% P

atie

nts

Course 1

Course 2

12 weeks 24 weeks

Infusion Associated Events withRetreatment

0

5

10

15

20

25

30

C1 N 1039 C2 N 570 C3 N 191 C4 N 40

1st INF

2nd INF

0

1

2

3

4

5

C1 C2 C3 C4

% Infusion Events

% Serious Events

C1

N 1039

C2

N 570

C3

N 191

C4

N 40

1st Infusion

Any AE 269 81 20 6

Total AE 446 104 26 7

SAE 5 1 0 0

Severe 11 2 0 0

Life Threatening 1 0 0 0

Dose Modification 100 32 6 4

D/C 12 0 0 0

2nd Infusion

Any AE 95 30 4 1

Total AE 124 39 5 1

SAE 2 1 0 0

Severe 1 1 0 0



D/C 0 1 0 0


0

0.5

1

1.5

2

2.5

0 4 8 12 16 20 24

Weeks

Mea

n I

gM

(m

g/m

L)

IgM

0

3

6

9

12

15

0 4 8 12 16 20 24

Weeks

Mea

n I

gG

(m

g/m

L)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

0 4 8 12 16 20 24

Weeks

Mea

n I

gA

(m

g/m

L)

IgG IgA

Placebo + MTX (n = 201) Rituxan + MTX (n = 298)

REFLEX Trial: Mean (SD) Serum Immunoglobulin Levels

SD = standard deviation.Cohen S et al. Arthritis Rheum. 2006;54:2793-2806.

LLN

Subanalysis: Retreatment B-Cell and Immunoglobulin Levels Relation to

Infections

Near-complete CD19+ B-cell depletion

Prior to C2 and C3

• 72% of patients < LLN

• B-cell repletion did not begin until at least Week 24

SIE similar in patients with normal IgG and IgM vs those with levels < LLN

Genovese M et al. Arthritis Rheum. 2006;54(9 suppl):S779 [abstract 1983].

All

N = 1039

Normal

IgM/IgG

N = 804

IgM < LLN

N = 207

IgG < LLN

N = 50

Years exposure 1670 1225 1376 125

SIE [N,(%)] 68 (6.5) 45 (5.6) 18 (8.7) 6 (12)

AE 84 58 21 6

SIE/100 pt-yrs 5.0 4.7 5.6 4.8

C1 C2 C3

IgM < LLN 8%–10% 18%–19% 22%–23%

IgG < LLN 0.5%–1.5% 4% 5%–6%

SIE with Use of TNF Inhibitors After Rituximab Therapy

78 patients treated with an anti-TNF after RTX• All had peripheral B-cell counts below LLN

14 (18%) had 22 AE• 10 SAE (3 RA flare, 2 pleuritis, 1 DVT, 4 SIE)

SIE• 2 skin (erysipelas, cellulitis)

• 1 bacterial arthritis

• 1 aseptic meningitis Rate of SIE

• After anti-TNF = 7.62 events/100 pt-yrs

• Before anti-TNF = 5.23 events/100 pt-yrs

Genovese M et al. Arthritis Rheum. 2006;54(9 suppl):S329 [abstract 726].

1

10

100

1000

10000

0 4 8 12

Month

Rit

uxi

mab

(m

ean

in n

g/m

L)

High HACA

No or low HACA

HACAs = more rapid rituximab pharmacokinetics

Rheumatology 2001; 40: 205-211

Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes

J. C. W. Edwards and G. Cambridge University College London Centre for Rheumatology, London, UK

Arthritis & Rheumatism, Oct 2002

An open study of B lymphocyte depletion in systemic lupus erythematosusMaria J. Leandro *, Jonathan C. Edwards, Geraldine Cambridge, Michael R. Ehrenstein,

David A. IsenbergMiddlesex Hospital, University College, London, UK

Arthritis & Rheumatism, Oct 2001

B lymphocyte depletion as a novel treatment for Systemic Lupus Erythematosus: Phase I/II trial of Rituximab (Rituxan) in SLEJennifer Anolik, Joe Rosenblatt, Fay Young, Iñaki Sanz, John LooneyUniversity of Rochester School of Medicine, Rochester, New York, USA

Arthritis & Rheumatism, 2004

B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab R. John Looney, Jennifer H. Anolik, Debbie Campbell, Raymond E. Felgar,

Faith Young, Lois J. Arend, James A. Sloand, Joseph Rosenblatt, Iñaki Sanz University of Rochester School of Medicine, Rochester, New York, USA

Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis

Jonathan C.W. Edwards, M.D., Leszek Szczepanski, M.D., Ph.D., Jacek Szechinski, M.D., Ph.D., Anna Filipowicz-Sosnowska, M.D., Ph.D., Paul Emery, M.D., David R. Close, Ph.D., Randall M. Stevens, M.D., and Tim Shaw, B.Sc.

New England Journal of Medicine, 2004

REFLEX Trial: Change inRadiographic End Points at Week 56 Is Not Dependent on Clinical Response at

Week 24

2.39

0.93

1.46

0.93

0.44 0.49

0.0

0.5

1.0

1.5

2.0

2.5

Total Genant Score Joint SpaceNarrowing

Erosion Score


Subgroup analysis of patients who were ACR20 nonresponders at Week 24 was also conducted using imputation for all withdrawals/rescue patients prior to Week 24.


P = 0.0271

P = 0.0396

P = 0.0126

Mea

n C

han

ge

ACR20 nonresponders at Week 24

Blood, Jan 1994

Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20

ME Reff, K Carner, KS Chambers, PC Chinn, JE Leonard, R Raab, RA Newman, N Hanna and DR Anderson

IDEC Pharmaceuticals Corporation, San Diego, CA 92121.

Blood, Sept 1997

IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With Relapsed Low-Grade Non-Hodgkin's Lymphoma

David G. Maloney, Antonio J. Grillo-López, Christine A. White, David Bodkin, Russell J. Schilder, James A. Neidhart, Nalini Janakiraman, Kenneth A. Foon, Tina-Marie Liles,

Brian K. Dallaire, Ken Wey, Ivor Royston, Thomas Davis, and Ronald Levy Stanford University, Stanford, CA

Blood, Feb 1987

Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas OW Press, F Appelbaum, JA Ledbetter, PJ Martin, J Zarling, P Kidd and ED Thomas

University of Washington: the Fred Hutchinson Cancer Research Center andOncogen Inc. Seattle Washington.


1. Infusion reactions:1. Frequent in lymphoma and SLE2. Rare in other diseases including RA3. Usually mild (NCI grade 1-2), mostly with first infusion4. May be due to lymphocyte (tumor) lysis or serum sickness-like

disease due to HACA2. Infections

1. Not increased2. Usually common and mild infections3. However, fulminant hepatitis B reactivation and PML have been

reported3. Hypo-gammaglobulinemia: rare may require IVIG replacement4. Late-onset neutropenia: uncommon (10%), transient, responds to GM-

CSF, may preclude further treatment

Chronic B cell depletion as maintenance therapy

•Which diseases: •Lymphoma, CLL•Rheumatoid Arthritis•SLE subset

Infusion Associated Events withRetreatment

0

5

10

15

20

25

30

C1 N 1039 C2 N 570 C3 N 191 C4 N 40

1st INF

2nd INF

0

1

2

3

4

5

C1 C2 C3 C4

% Infusion Events

% Serious Events

C1

N 1039

C2

N 570

C3

N 191

C4

N 40

1st Infusion

Any AE 269 81 20 6

Total AE 446 104 26 7

SAE 5 1 0 0

Severe 11 2 0 0



D/C 12 0 0 0

2nd Infusion

Any AE 95 30 4 1

Total AE 124 39 5 1

SAE 2 1 0 0

Severe 1 1 0 0



D/C 0 1 0 0


Rituximab in Rheumatoid Rituximab in Rheumatoid ArthritisArthritis

Baseline 48 weeks

Rituximab (1g x 2)

Rituximab (1g x 2) Cytoxan (750 mg x 2)

MTX ( >10mg/wk)

Rituximab (1g x 2)

MTX ( > 10 mg/wk)

MTX inadequateresponders

RANDOMIZED

17 day corticosteroids

in all arms

Edwards et al. NEJM 2004

ACR Response at 24 weeks

0

20

40

60

80

100

MTX Rituximab Rituximab +CTX

Rituximab +MTX

% p

atie

nts ACR20

ACR50

ACR70

p = 0.025 P = 0.001 P = 0.003

P = 0.005 P = 0.005

P = 0.048

Rituximab in rheumatoid arthritis: efficacy and safety from a randomised controlled

trial. Stahl et al. Ann Rheum Dis 2003, 62 (Suppl): 0P004.

ACR Response at 48 weeks

0

20

40

60

80

100

MTX Rituximab Rituximab +CTX

Rituximab +MTX

% p

atie

nts

ACR20

ACR50

ACR70

P = 0.0001

P = 0.002

P = 0.03

P = 0.01

P = 0.01

Phase I/II Open-label Dose-escalating Phase I/II Open-label Dose-escalating Trial of Rituximab in Patients With Trial of Rituximab in Patients With

SLESLE

Dose escalation: 6 subjects per group

one dose of 100 mg/m2 rituximab

one dose of 375 mg/m2 rituximab

four weekly doses of 375 mg/m2 rituximab

Efficacy outcomes:

B cell depletion

SLAM

Serology

Clinical Response in Clinical Response in SLESLE

****

0 Months 1 Month 2 Months 3 Months

Non-depleters (n=6)

Depleters (n=10)

02468

1012141618

SLA

M (

mea

n an

d 95

% C

I)

Looney, Anolik et al. Arthritis and Rheum 50:2580, 2004

Anolik et al. Arthritis & Rheumatism, 2004, 50:3580.

Clinical response is independent Clinical response is independent of serological responseof serological response

1

10

100

0 1 2 3 6 9 12 360

20

40

60

80

100

120

140

160

180

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Months post-Rx: #4 low dose

Months post-Rx: #15 high dose

1000

0.10

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0 1 2 3 6 9 12 20 240

50

100

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200

250

Per

cen

t o

f b

asel

ine

Ab

solu

te B

cel

l #

Months post-Rx: #1 low dose

1

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0 1 2 3 6 9 12 360

20

40

60

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160

B cell countB cell countSLAM index Anti-ds DNAAnti-ds DNA

Anti-dsDNA in depletersAnti-dsDNA in depleters

1

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0 1 2 3

Month

An

ti-d

sD

NA

aspectos patogénicos y terapéuticos de los linfocitos b. presente y futuro division of clinical...

Documents

surface of b

cellsmarkers of b

b cells important

clinical trialresponse

complete clinical remission

lowdose rituximab single

multiple autoimmune

conventional therapy