anti tnf therapy in rheumatoid arthritis prof. marc feldmann · the screen versions of these slides...

Anti TNF Therapy

in Rheumatoid Arthritis

Prof. Marc Feldmann

The screen versions of these slides have full details of copyright and acknowledgements 1

1

Kennedy Institute of Rheumatology Division Kennedy Institute of Rheumatology Division Kennedy Institute of Rheumatology Division Kennedy Institute of Rheumatology Division F aculty of MedicineF aculty of MedicineF aculty of MedicineF aculty of Medicine

Anti TNF Therapy in Rheumatoid Arthritis

Marc Feldmann

Imperial CollegeLondon

Supported by

2

TNF: historyTumour necrosis Cachexia

Carswell et al., 1975 PNAS 72727272: 3666

Inflammation

Leucocyte recruitmentVascular damage and leak

e.g., trypanosomasis,cancer, catabolic state

muscle wasting, anaemia

A. Cerami

Cloning of TNFPennica et al., 1984, NatureBeutler et al., 1985, Nature

3

Why look for cytokines in rheumatoid arthritis?U pregulation of HLAU pregulation of HLAU pregulation of HLAU pregulation of HLA----DR in rheumatoid synoviumDR in rheumatoid synoviumDR in rheumatoid synoviumDR in rheumatoid synovium

(Klareskog, Wigzell, Panayi, Janossy etc. 1981/82)

Rheumatoid arthritis Osteoarthritis

Expression of HLA-DR on cells usually negative

indicates presence of inducers = cytokines

Anti TNF Therapy


Prof. Marc Feldmann


4

Establishing the conceptEstablishing the conceptEstablishing the conceptEstablishing the conceptTesting the conceptTesting the conceptTesting the conceptTesting the concept

Londei et al., 1985, ScienceHuman T-cell clones from autoimmune

thyroid glands: specific recognition of autologous thyroid cells

InterferonInterferonInterferonInterferon& t i ssue damage& t i ssue damage& t i ssue damage& t i ssue damage

AutoantibodiesAutoantibodiesAutoantibodiesAutoantibodiesand t issue damageand t issue damageand t issue damageand t issue damage

Vi rusesVi rusesVi rusesVi ruses

C ytokinesC ytokinesC ytokinesC ytokines


The concept

TTTT

Upregulation of HLA class II and antigen presentation

No n tolerant No n tolerant No n tolerant No n tolerant a u toantigen a u toantigen a u toantigen a u toantigen

re activere activere activere activeT c ellsT c ellsT c ellsT c ells

TTTT

BBBB

APCAPCAPCAPC


Marco Londei

Londei et al., 1984, NatureEpithelial cells expressing aberrant MHC class II determinants can present antigen to cloned human T cells

Pujol-Borrell et al., 1987, NatureHLA class II induction

in human islet cells by interferon-γ

plus TNF or lymphotoxin

5

APC Thyroid PBMC IL-2 AlloTh- -

T cells + + + + +

Restimulation of autoantigen reactiveT cells in diseased tissue

Londei, Bottazzo and Feldmann(1985) Science 228228228228: 85-89

6

Testing the concept: mediators

Dilemma:

1. Cytokine expression in thyroid

cannot be tested in active disease

2. Little unmet medical need

Tiny Maini

Solution:

Rheumatoid arthritis

and collaboration with Tiny Maini

Anti TNF Therapy


Prof. Marc Feldmann


7

Many cytokines are produced in rheumatoid synovium

Are any therapeutic targets?

Pro-inflammatory

e.g., IL-1, IL-6, TNFα, IL-12, IL-15, IL-17, IL-18,

IFNγ, IL-2, OncoM, GM-CSF

Anti-inflammatory

e.g., IL-10, IL-1Ra, TGFβ, IL-11, IL-13

Chemokines

e.g., IL-8, MIP-1α, MCP-1, RANTES, ENA-78, GROα

Growth Factors

e.g., VEGF, PDGF, FGF

8

Prolonged synthesis of IL-1αin rheumatoid synovium

0

1

2

3

4

5

6

1 2 3 4 50

IL-1αα ααmRNA

(units*)

Time (days)

Buchan et al., (1988) Clin Exp Immunol 73737373:449

Normal

Glenn Buchan * 1 unit = normal blood response to LPS

A l l curves are ILA l l curves are ILA l l curves are ILA l l curves are IL----1111αααα mRNAmRNAmRNAmRNAf rom different patients synovium or normalf rom different patients synovium or normalf rom different patients synovium or normalf rom different patients synovium or normal

9

Analysis of cytokine regulationrevealed importance of tumour necrosis factor

ApproachApproachApproachApproachOperative sample synovium,active RA cells isolated, placed in ‘tissue culture’ObservationObservationObservationObservationSpontaneous production of many mediators of disease-cytokines, enzymes etc.

Brennan et al. (1989) Lancet II 244-247

6310

10

20

30

control

anti LT

anti TNFα

IL-1

(U/m

l)

Days of culture

Rh eumatoid arthritisRh eumatoid arthritisRh eumatoid arthritisRh eumatoid arthritis Os t eoarthritisOs t eoarthritisOs t eoarthritisOs t eoarthritis

6310.00.20.40.60.81.0

Days of culture

IL-1

(U/m

l)

Fionula Brennan

ExperimentExperimentExperimentExperimentAntibody to TNF inhibitsproduction of otherpro-inflammatory cytokines

Anti TNF Therapy


Prof. Marc Feldmann


10

A useful oversimplification….

Cytokine cascade in rheumatoid arthritis

Immune system TNTNTNTNFFFFα

Anti-inflammatory

IL-10, IL-1rα, sTNF-R

Pro-inflammatory

IL-6, IL-8, GM-CSF etc.

IL-1

Feldmann, Brennan and Maini (1996) Cell, 85858585: 307

11

TNF is early onset Anti-TNF diminishes IL-1 and IL-6

0000 1111 2222 3333 4444 5555 6666Hour sHour sHour sHour s

0000 1111 2222 3333 4444 5555 6666Hour sHour sHour sHour s

TNFTNFTNFTNF

I LI LI LI L ---- 1111

I LI LI LI L ---- 6666

I LI LI LI L ---- 6666

I LI LI LI L ---- 1111

I LI LI LI L ---- 1+TNF1+TNF1+TNF1+TNFα I LI LI LI L ---- 6+TNF6+TNF6+TNF6+TNFα

Adapted from Fong et al., J. Exp. Med. 170170170170: 1627 (1989)

Cytokine cascade is physiological:occurs in response to infection

12

ModelGenetically susceptible mice (DBA/1) Injected collagen type II(major constituent cartilage)About 21 days later arthritis appearsand then spreads joints destroyed

TNF blockade protects joints in an animal model of rheumatoid arthritis

A nt iA nt iA nt iA nt i----TNF treatedTNF treatedTNF treatedTNF treated

I s otype IgG controlI s otype IgG controlI s otype IgG controlI s otype IgG control

Nor m alNor m alNor m alNor m alWilliams, Feldmann, Maini (1992)

Proc Natl Acad Sci (USA) 89898989, 9784

Histology

Results

0000 2222 4444 6666 8888 10101010 12121212 14141414Days after onset of arthritis

A n t iA n t iA n t iA n t i ----TNF (500 TNF (500 TNF (500 TNF (500 µµµµg)g)g)g)



control

Paw

thick

ness

(% in

crem

ent)

0000

10101010

2020202030303030

40404040

50505050

60606060

70707070

Richard Williams Bob Schreieber

Anti TNF Therapy


Prof. Marc Feldmann


13

Rationale for anti-TNFαααα therapy in rheumatoid arthritis

1. Disregulated cytokine network in RA synovium

is dependent on TNFα

2. TNFα/TNF-receptor upregulated in synovium

3. Animal model of RA responds very well to anti-TNFα administered after disease onset

14

From bench to bedside

• Jim Woody at Centocor agreed to help

• Clinical trial with cA2 (now infliximab)

started in May 1992 at CX Hospital

• By 1991 the stage was set for clinical translation

• Due to Cerami’s concept of TNF driving

sepsis anti-TNF antibodies had been made

Jim Woody

15

Remicade® (infliximab)

Knight DM et al., Mol Immunol., 1993; 16161616: 1443-1453

Jan Vilcek

John Ghrayeb

Harlan Weissman

• Chimeric IgG1

monoclonal antibody

• High affinity binding

to TNFα (Ka = 1010M-1)

• Administered

by intravenousinfusion over 1 hourevery 8 weeks

Anti TNF Therapy


Prof. Marc Feldmann


16

p < 0 .00 1 0.0 01 0 .00 2 0. 02 0 .00 1 0.0 01p < 0 .00 1 0.0 01 0 .00 2 0. 02 0 .00 1 0.0 01p < 0 .00 1 0.0 01 0 .00 2 0. 02 0 .00 1 0.0 01p < 0 .00 1 0.0 01 0 .00 2 0. 02 0 .00 1 0.0 01

0000

2 02 02 02 0

4 04 04 04 0

6 06 06 06 0

8 08 08 08 0

1 0 01 0 01 0 01 0 0

1 2 01 2 01 2 01 2 0

W eeksW eeksW eeksW eeksSc reenSc reenSc reenSc reen0000 1111 2222 3333 4444 6666 8888

CRPp < 0 .01 0.0 01 0 .00 1 0.0 01 0 .00 1p < 0 .01 0.0 01 0 .00 1 0.0 01 0 .00 1p < 0 .01 0.0 01 0 .00 1 0.0 01 0 .00 1p < 0 .01 0.0 01 0 .00 1 0.0 01 0 .00 1

Sc reenSc reenSc reenSc reen 0000 1111 2222 3333 4444 6666 8888

Swollen joint count

ResultsW e llW e llW e llW e ll ---- toleratedtoleratedtoleratedtoleratedUn i versal clinical responseUn i versal clinical responseUn i versal clinical responseUn i versal clinical responseRa p id suppression ESR and CRPRa p id suppression ESR and CRPRa p id suppression ESR and CRPRa p id suppression ESR and CRPNo n o n respondersNo n o n respondersNo n o n respondersNo n o n responders

In f l ix imab: 20 mg/kg In f l ix imab: 20 mg/kg In f l ix imab: 20 mg/kg In f l ix imab: 20 mg/kg ( total)( total)( total)( total)

W e ek W e ek W e ek W e ek ----4444 0000 2222 4444 6666 8888

An a lysisAn a lysisAn a lysisAn a lysis

wa shoutwa shoutwa shoutwa shout

Design

0000

4444

8888

1 21 21 21 2

1 61 61 61 6

2 02 02 02 0

2 42 42 42 42 82 82 82 8

Open-label treatment with infliximab in rheumatoid arthritis

Elliott, Maini, Feldmann et al., Arthritis Rheum 1993, 36363636: 1681-90

(mg/l)

W eeksW eeksW eeksW eeks

17

Randomised, placebo-controlled trialof infliximab in rheumatoid arthritis

R esultsR esultsR esultsR esultsWell-toleratedGood clinical responses in cA2 groupsDose-response relationship

DDDD es ignes ignes ignes ign

3, 10 or 20 mg/kg3, 10 or 20 mg/kg3, 10 or 20 mg/kg3, 10 or 20 mg/kg1 or 10 mg/kg1 or 10 mg/kg1 or 10 mg/kg1 or 10 mg/kgor HSAor HSAor HSAor HSA

Week -4 0 4

washout

c A 2:c A 2:c A 2:c A 2:

Elliott, Maini, Feldmann et al., Lancet 1994; 344: 1105-10

Placebo

1 mg/kg cA2

10 mg/kg cA2

4321000

10

20

30

40

50

60

70

80

Week

normal range

p<0.001

p<0.01

CRP

4321000

10

20

30

Week

Swollen joint count

p<0.001p<0.001

44%

8%

79%

1 mg/kg

Placebo

10 mg/kg

Responders

Non-responders

p=0.0083

p<0.0001

Paulus 20% responses at week 4Ferry Breedveld

Jochen Kalden

Josef Smolen

(mg/l)

18

Early evidence of efficacy of repeated infliximab therapy

Swollen

joint

count

(0-28)

CRP

(mg/l)

6050403020100-100

10

20

0

10

20

30

40

50

60

70

Week

1020 10 10

Dose infliximab (mg/kg)

Elliott, Maini, Feldmann et al. Lancet 1994; 344344344344:1125

Anti TNF Therapy


Prof. Marc Feldmann


19

Combination therapy - sub-optimal

anti-TNF plus anti-CD4

Time, days0000 1111 2222 3333 4444 5555 6666 7777 8888 9999 10101010

1.41.41.41.4

1.51.51.51.5

1.61.61.61.6

1.71.71.71.7

1.81.81.81.8

1.91.91.91.9

2.02.02.02.0

2.12.12.12.1

****

Williams et al., Proc Nat Acad Sci 91919191:2762-2766 (1994)

Paw

thic

knes

s m

m

C ontrol mAb C ontrol mAb C ontrol mAb C ontrol mAb

AntiAntiAntiAnti----TNF + TNF + TNF + TNF + ant i CD4 ant i CD4 ant i CD4 ant i CD4 Ant iAnt iAnt iAnt i----CD4 CD4 CD4 CD4

al one al one al one al one

Ant iAnt iAnt iAnt i----TNFTNFTNFTNF

* p < 0.05

20

% p

atie

nts

resp

ondi

ng

1 mg/kg cA2 3 mg/kg cA2 10 mg/kg cA2

Week

Paulus 50% responses to infliximab

60

80

40

20

0

20

60

80

40

0

0 4 8 12 16 26 0 4 8 12 16 26 Week0 4 8 12 16 26

100 100

Placebo MTX+ cA2 MTX- cA2 MTX+

Maini RN et al., (1998) Arthritis Rheum.; 41414141: 1552-1563

±±±±methotrexate: synergy

21Maini RN et al., (1998) Arthritis Rheum. 41414141:1552

Rationale of combination infliximab and MTX

100

75

50

25

0

(% o

f pat

ient

s)

Infliximab dose (mg/kg)1 3 10

Antibodies to infliximab

InfliximabInfliximab + MTX

Weeks

10

Seru

m in

flixi

mab

(mg/

ml)

0

51 mg/kg

100

75

50

25

00 2 6 1410 18 2622

10 mg/kg

3 mg/kg

20

15

10

5

Pharmacokineti cs

Anti TNF Therapy


Prof. Marc Feldmann


22

Attract: sustained prevention of structural damage

0.64.8 1.0 -0.5 -0.31.3 1.6 0.2-0.7

7.0 1.0 1.0 1.1 -0.412.6

-3

0

3

6

9

12

15

18

+ MTXPlacebo Infliximab

3mg/kg

q 8 wks

Infliximab 3mg/kg

q 4 wks

Infliximab 10mg/kg

q 8 wks

Mean (SE) change from baseline

0 - 30 Weeks

0 - 54 Weeks

0 - 102 Weeks

+ MTX + MTX + MTX

Infliximab 10mg/kg

q 4 wks

+ MTX

Lipsky et al., (2000) NEJM 343343343343(22): 1594

Peter Lipsky

At t ractA t t ractA t t ractA t t ract

23

Reversal of structural damage

Infliximab Infliximab Infliximab InfliximabPlacebo

+ MTX

+ MTX + MTX + MTX + MTX

*

Negative change in modified sharp score at week 54

p-value vs. MTX <0.001 <0.001 <0.001 <0.001

14%

45%

49%

39%

54%

0%

10%

20%

30%

40%

50%

60%

3 mg/kg q 8 wks

3 mg/kg q 4 wks

10 mg/kg q 8 wks

10 mg/kg q 4 wks

Percent with improvement

At t ractA t t ractA t t ractA t t ract

24

Combination of etanercept and methotrexateis more effective (tempo)

Reproduced from: Klareskog et al., (2004)Lancet 3 633 633 633 63: 675Therapeutic effect of the combinationof etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial

Lars Klareskog

Time (months) 121

Time (months)126

Anti TNF Therapy


Prof. Marc Feldmann


25

Summary of anti-TNF therapy in rheumatoid arthritis

1. Control of symptoms: pain, stiffness, fatigue

2. Control of signs: swelling, tenderness

3. Control of joint destruction

4. Initiation of joint repair: reduced sharp score

5. Improvement in health (HAQ)

6. Approaching 106 treated patients

7. Long term benefit

26

Antibody based therapeutic proteins can be used for many years

27Breedveld FC, et al., Arthritis Rheum., 2003; 48 48 48 48 (Suppl):S118 [Abstract 198]

Months

% of patients

(n = 53) (n = 36)

6862

75

63

77

3036

50 50 46

8 11

2824 22

010

203040

5060

7080

12 24 36 48 60

ACR-20

ACR-50

ACR-70

18% retention18% retention18% retention18% retentionat 5 yearsat 5 yearsat 5 yearsat 5 years

Bob Kamen Jeff Leiden

Adalimumab (Humira) + MTX:sustained efficacy over 5 years

Anti TNF Therapy


Prof. Marc Feldmann


28From: Moreland et al., ACR 2004

7 years of etanercept therapy

29

Verifying mechanismof action in phase II useful

30Charles et al., (1999) J Immunol; 163163163163: 1521-28

Day282170 141 3

0

100

200

150

50

Ser

um IL

-6 (p

g/m

l)

P l aceboP l aceboP l aceboP l acebo1 m g/kg1 m g/kg1 m g/kg1 m g/kg1 0 mg/kg1 0 mg/kg1 0 mg/kg1 0 mg/kg

TNFα dependent cytokine cascadeis operative in vivo

Anti TNF Therapy


Prof. Marc Feldmann


31

Other cytokinesdown regulated also

e.g., IL-1, VEGF, MCP-1 etc.

32

TNF is the body’s fire alarm

Initiates leucocyte recruitment

33

3

TNFα blockade and inflammatory cell traffic - early clues

Paleolog et al., Arthritis Rheum 1996, 39393939; 1082

Weeks after infusion

†

0 1 2 3 4Pre-infusion

****

****** ***

***

***††

**

†††††††

†††

0

1

2

Lymphopenic range

Lym

phocyte

s x

10

9/l

H&E staining CD3+

Before

After

Tak, Taylor et al., Arthritis Rheum 1996, 39393939; 1077

10mg/kg anti-TNFαααα1mg/kg anti-TNFααααPlacebo

Pai red synovial biopsiesPai red synovial biopsiesPai red synovial biopsiesPai red synovial biopsies

Anti TNF Therapy


Prof. Marc Feldmann


34Knees Hands

Pre

-tre

atm

ent

2 w

eeks p

ost-

treatm

ent

Reduced PMN trafficking after infliximab therapy

Taylor et al., (2000) Arthritis Rheum 43434343:38-47R knee L Hand R handL knee

Perc

enta

ge c

hange

cpm

/pix

el

/MB

q

5

-5

-15

-25

-35

-45

-55

-65

Peter Taylor

35

Most chronic inflammatory diseases respond to anti-TNF

36

TNF is a good target in many chronic diseases

• Approved use

Rheumatoid arthritis, juvenile rheumatoid arthritis, Crohn’s,psoriatic arthritis, Ankylosing spondylitis, Psoriasis, ulcerative colitis

• Trials not completed and pilot studiesBehçet’s syndrome, vasculitis (wegeer’s and giant cell),

glomerulonephritis, SLE, joint prosthesis loosening, hepatitis, polymyositis, systemic sclerosis, amyloidosis, sarcoidosis, ovarian cancer, steroid resistant asthma, refractory uveitis

• Clinical failuresCongestive heart failure, multiple sclerosis, Sjogren’s syndrome

Common theme: inhibition leucocyte recruitment

Anti TNF Therapy


Prof. Marc Feldmann


37

-60

-50

-40

-30

-20

-10

0

+10

W e eks after infusionW e eks after infusionW e eks after infusionW e eks after infusion

P l aceboP l aceboP l aceboP l acebo

0000 1111 2222 3333 4444

1 m g/kg anti1 m g/kg anti1 m g/kg anti1 m g/kg anti ----TNFTNFTNFTNFαααα

1 0 mg/kg 1 0 mg/kg 1 0 mg/kg 1 0 mg/kg antiantiantianti ----TNFTNFTNFTNFαααα

Paleolog et al. (1998) Arthritis Rheum 41 41 41 41 1258-65

Decrease in serum VEGFafter single infusion of infliximab

von

Wille

bran

d fa

ctor

-pos

itive

vess

el co

unt/

field

Anti-TNFα reduces synovial vessel density

M e ans of 5M e ans of 5M e ans of 5M e ans of 5----8 fields per patient, 8 fields per patient, 8 fields per patient, 8 fields per patient, a d justed for the area of a single fielda d justed for the area of a single fielda d justed for the area of a single fielda d justed for the area of a single field

Pr ePr ePr ePr e Pos tPos tPos tPos t0

20406080

100120140160

Ballara, S. et al., (2001) A&R 44444444: 2055

Reduced angiogenesis after anti-TNF

Ewa Paleolog

38

1. Downregulati on of many proinflammatory cytokines in vivoIL-1, GM-CSF, IL-6, IL-8 and other chemoki nes (Feldmann et al., 1996)

2. Reduction in leukocyte traffickingReduction in adhesion molecul es and chemoki nes (Feldmann et al., 1997)

3. Reduction in angiogenesisReduction in VEGF (Paleolog et al., 1998)

4. Reduction in joint destructi onReduction in IL-1, MMPs �XR changes (Brennan et al., 1989, 1997, ACR 99)

5. Haematol ogi cal normalizationHaemogl obin �, platelets �, fibrinogen �: cardiovascular risk � ?

6. Others:Promotes apoptosi s (via Deventer, Klareskog)

Induces regulatory T cells (Ehrenstein et al., 2004)

Normalized T cell response to recall antigen (Cope, 1994)

How is cytokine washout with infliximab translated into clinical benefit?

Conclusion: TNFα close to core of disease

39

Nothing is perfect: problems

1. Efficacy

2. Safety:

Infection

Lymphomas

3. Cost

4. Convenience

Anti TNF Therapy


Prof. Marc Feldmann


40

Safety problems of TNF blockade

• Interferes host defence

• Infection TB < 1/2000Other opportunistic infections rarer

Common infection: URTI, pneumoniaInfected prosthesesHerpes Zoster

• B cell lymphomas

Quantifying frequency infection/B cell lymphomas

is difficult as rheumatoids have markedly increased risk, proportional disease severity

Safety needs to be seen

in context of reduced life span/life quality

41

Early treatment is more effective

BeSt Trial, Goekoop-Ruiterman….Breedveld …et al., 2005, A&R 52525252(11): 3381

Entry: active RA, median duration symptoms23 weeks, diagnosi s to inclusion 2 weeks

ACR70

Ferry Breedveld

05

1015

20

253035

40

45

3 6 9 12

Time, months (n)

Percentage

MonoStep-upCOBRAAnti-TNF

42From: Quinn and Emery et al., (2005) A&R 52525252: 27-35

Prolonged reduction in disease activity despite cessation of anti TNF

60% ACR 70 cf 0%

Paul Emery

Anti TNF Therapy


Prof. Marc Feldmann


43

Impact on medicine and research

1.1.1.1. New therapeutics for many diseases:New therapeutics for many diseases:New therapeutics for many diseases:New therapeutics for many diseases:

TNF as body’s fire alarm

2.2.2.2. Improvements in clinical trial designImprovements in clinical trial designImprovements in clinical trial designImprovements in clinical trial design,

speed, cost

3. Realization that profound joint protectionprofound joint protectionprofound joint protectionprofound joint protection

and even repair possible

4.4.4.4. Best resultsBest resultsBest resultsBest results

- EarlyEarlyEarlyEarly

- Combination with methotrexate

5.5.5.5. Importance of “translational research”:Importance of “translational research”:Importance of “translational research”:Importance of “translational research”:

Bench to bedside emphasized

44

Impact of TNF blockadeon pharmaceutical industry

1. Source of new therapeutics; commercial success

- 2 blockbusters (> $1bn/year) Remicade®, Enbrel®another soon (Humira®)

2. Appreciation that biologics can be used long term- For chronic diseases – less risk

3. Relative safety–mechanism related capacity to generate biologics- Almost half of all therapeutic candidates now biologics

4. Prime example of academic-industrial collaboration- Academic know how of disease, target, clinical needs

- Industrial capacity to make and develop therapeutic

45

Acknowledgements

Key external collaborators: reagents

Major contributors to relevant knowledge

Cloning TNF: D. Goeddel, P. Gray, B. Beutler

TNF biology: A. Cerami, C. Dinarello etc.

Tada

Taniguchi

Tadamitsu

Kishimoto

Mike

Shepard

Bob

Schreiber

Anti TNF Therapy


Prof. Marc Feldmann


46

Acknowledgements

Preclinical: key internal collaborators

D r Glenn Buchan team: D r Glenn Buchan team: D r Glenn Buchan team: D r Glenn Buchan team: Maija KissonerghisKatherine Barrett

Ini tial gene expression Ini tial gene expression Ini tial gene expression Ini tial gene expression i n j ointsi n j ointsi n j ointsi n j oints

Pr of. Fionula Brennan team:Pr of. Fionula Brennan team:Pr of. Fionula Brennan team:Pr of. Fionula Brennan team:David ChantryMartin Turner

Gene regulation in joints:Gene regulation in joints:Gene regulation in joints:Gene regulation in joints:T N F as pivotal cytokineT N F as pivotal cytokineT N F as pivotal cytokineT N F as pivotal cytokine

D r Richard Williams team:D r Richard Williams team:D r Richard Williams team:D r Richard Williams team:Lesley Mason

Amelioration of collagenAmelioration of collagenAmelioration of collagenAmelioration of collageni nduced arthritis i nduced arthritis i nduced arthritis i nduced arthritis

by anti TNF antibodyby anti TNF antibodyby anti TNF antibodyby anti TNF antibody

D r Ewa Paleolog team:D r Ewa Paleolog team:D r Ewa Paleolog team:D r Ewa Paleolog team:Sylvia YoungAngela Stark

R ol e of VEGF in arthritisR ol e of VEGF in arthritisR ol e of VEGF in arthritisR ol e of VEGF in arthritis

Clinical triallists: Elliott, Taylor, Woody, Weisman,

Breedveld, Kalden, Smolen, Lipsky, St Clair, Emery etc.

47

Acknowledgements

Sir Ravinder Maini

48

Acknowledgements: funding

arcKennedy Trust

Nuffield FoundationWellcome Trust

US NavyCentocor

Anti TNF Therapy


Prof. Marc Feldmann


49

anti tnf therapy in rheumatoid arthritis prof. marc feldmann · the screen versions of these slides...

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