Mabthera treatment modulates cell types other than b cells
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MabThera treatment modulates cell types other than B cells. Professor Paul-Peter Tak Academic Medical Center (AMC)/University of Amsterdam, Amsterdam, the Netherlands. Marked B cell depletion after anti-CD20 therapy. 200. CONTROL. +R. +R+CTX. 150. +R+MTX. Median CD19+ B cells per mm 3.

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MabThera treatment modulates cell types other than B cells

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Mabthera treatment modulates cell types other than b cells

MabThera treatment modulates cell types other than B cells

Professor Paul-Peter Tak

Academic Medical Center (AMC)/University of Amsterdam, Amsterdam, the Netherlands


Marked b cell depletion after anti cd20 therapy

Marked B cell depletion after anti-CD20 therapy

200

CONTROL

+R

+R+CTX

150

+R+MTX

Median CD19+ B cells per mm3

100

50

0

0

4

8

12

16

20

24

Time (weeks)

Edwards JC et al. N Engl J Med. 2004;17;350:2572-81


Synovial tissue primary target of ra

Synovial tissue: Primary target of RA

Analysis of the

target tissue

Choy E et al. N Engl J Med. 2001;344:907–16


Synovial tissue response to rituximab

Synovial tissue response to rituximab

Open label

17 patients with RA, IgM-RF+ and/or ACPA+

Stable MTX treatment, oral prednisone allowed up to 10 mg/day

Previous treatment with anti-TNF allowed (washout)

Vos K et al. Arthritis Rheum 2007;56:772-8


Treatment

Treatment

  • 2 infusions of 1000 mg rituximab in 2 weeks

  • No methylprednisolone pre-medication

    • Steroids reduce synovial inflammation

Vos K et al. Arthritis Rheum 2007;56:772-8


Change in cd22 b cells of individual patients before and 4 weeks after treatment

Before

After

Change in CD22+ B cells of individual patients before and 4 weeks after treatment

1100

1000

900

Values for number of CD22+ B cells/mm2 in serial synovialtissue samples are shown for individual patients

800

700

Number of CD22+ B cells (mm2)

350

300

250

200

150

100

50

0

Vos K et al. Arthritis Rheum 2007;56:772-8


Mabthera treatment modulates cell types other than b cells

Change in CD22+ synovial B cells 4 weeks after treatment with rituximab

Before

After

Patient 1

Patient 2


Change in number of synovial cd22 b cells and cd3 t cells after rituximab treatment

**

Baseline

Baseline

Week 16

Week 4

Week 4

Change in number of synovial CD22+ B cells and CD3+ T cells after rituximab treatment

**

800

1500

*

1200

600

900

Number of CD22+ B cells (mm2)

Number of CD3+ T cells (mm2)

400

600

200

300

0

0

Week 16

Interquartile ranges. Circles represent outliers *p<0.05,**p<0.01

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Mabthera treatment modulates cell types other than b cells

Change in number of synovial lymphocyte aggregates and CD68+ intimal macrophages after rituximab treatment

*

**

**

125

1000

100

800

600

75

Number of CD68+ intimal macrophages (mm2)

Total number of lymphocyte aggregates

400

50

200

25

0

0

Baseline

Week 4

Week 16

Baseline

Week 4

Week 16

Interquartile ranges. Circles represent outliers *p<0.05,**p<0.01

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Mabthera treatment modulates cell types other than b cells

Change in number of synovial sublining CD68+ macrophages and CD138+ plasma cells after rituximab treatment

*

1400

2500

1200

2000

1000

1500

800

Number of CD68+ sublining macrophages (mm2)

Number of CD138+ plasma cells (mm2)

600

1000

400

500

200

0

0

Baseline

Week 4

Week 16

Baseline

Week 4

Week 16

Interquartile ranges. Circles represent outliers *p<0.05

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Synovial tissue response to rituximab treatment

Synovial tissue response to rituximab treatment

  • Variable response of synovial B cells

  • Secondary effects on cells other than B cells

    • B cells orchestrate synovial inflammation


Is the synovial tissue response predictive of the clinical response to rituximab treatment

Is the synovial tissue response predictive of the clinical response to rituximab treatment?


Mabthera treatment modulates cell types other than b cells

The number of synovial B cells at baseline is not predictive of the clinical response to rituximab treatment

800

600

Number of CD22+ B cells (mm2)

400

200

0

Non-responders

Responders

Interquartile ranges. Circles represent outliers

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


The change in synovial b cells is not predictive of the clinical response to rituximab treatment

Change in B cells

(baseline–Week 4)

Change in B cells

(Weeks 4–16)

400

400

200

200

0

0

Number of CD22+ B cells (mm2)

Number of CD22+ B cells (mm2)

-200

-200

-400

-400

Non-responders

Responders

Non-responders

Responders

The change in synovial B cells is not predictive of the clinical response to rituximab treatment

Interquartile ranges. Circles represent outliers

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Mabthera treatment modulates cell types other than b cells

Baseline plasma cells

Baseline intimal macrophages

1000

800

800

600

600

Number of CD68+ intimal

macrophages (mm2)

Number of CD138+ plasma cells (mm2)

400

400

200

200

0

0

Non-responders

Responders

Non-responders

Responders

The number of synovial plasma cells or intimal macrophages at baseline is not predictive of the clinical response to rituximab treatment

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Mabthera treatment modulates cell types other than b cells

1000

500

500

0

0

-500

-500

-1000

Non-responders

Responders

Non-responders

Responders

Changes in synovial plasma cells and intimal macrophages are predictive of the clinical response to rituximab treatment

Change in plasma cells

(Weeks 4–16)

Change in intimal macrophages

(Weeks 4–16)

**

**

Number of CD68+ intimal

macrophages (mm2)

Number of CD138+ plasma cells (mm2)

Interquartile ranges. Circles represent outliers *p<0.05

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Change in synovial plasma cells is related to clinical improvement

Change in synovial plasma cells is related to clinical improvement

4 weeks after treatment

16 weeks after treatment

Responder

Non-responder

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Mabthera treatment modulates cell types other than b cells

Relationship between changes in the synovium between 4 and 16 weeks and clinical response at24 weeks

  • Correlation between changes in the synovium and clinical response:

    • Plasma cells: r=0.46, p=0.003

    • Macrophages: r=0.51, p=0.04

  • Decrease in plasma cells predicts clinical response (r2=0.26, p=0.002)

    • Change in plasma cells was correlated with decrease in ACPA levels (r=0.52, p=0.03)


Significant decrease in igm rf and acpa levels after rituximab treatment

ACPA

*

3000

2000

ACPA titre (kU/L)

1000

0

Week 4

Baseline

Week 16

Week 24

Week 36

Significant decrease in IgM-RF and ACPA levels after rituximab treatment

IgM-RF

**

800

**

600

IgM-RF titre (kU/L)

400

200

0

Week 4

Baseline

Week 16

Week 24

Week 36

Interquartile ranges. Circles represent outliers *p<0.05,**p<0.01

Thurlings RM et al. Ann Rheum Dis 2008;67:917-25


Benefit of retreatment

B cell-derived plasma cells may be associated with autoimmunity in the tissue of patients who do not experience a clinical response to the first course of rituximab

Benefit of retreatment?


Sustained benefit from das28 based systematic retreatment in initial responders

8

6

DAS28

4

2

0

3

6

9

12

15

18

21

24

Baseline

Time (months)

Sustained benefit from DAS28-based systematic retreatment in initial responders

n=16

Thurlings RM et al. Arthritis Rheum 2008;58:3657-64


Conclusions

Conclusions

  • B cells appear to orchestrate local cellular infiltration

  • Kinetics of the serological and tissue response suggest that rituximab exerts its effects, in part, by an indirect effect on B cell-derived plasma cells associated with autoantibody production

    • Initial responders to rituximab experience sustained benefit from DAS28-based systematic retreatment

  • Rituximab does not induce robust improvement after retreatment of initial non-responders


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