Aims of talk

1
Aims of talk

• RA is a serious disease
• Convince you that it is driven by T-cells
• Cyclosporin first proof of concept of the
• T-cell hypothesis
• Developments since Cyclosporin

2
Synopsis of talk

• What is rheumatoid arthritis
• Pathogenesis of the synovitis
• Mechanism of bone damage
• CsA as model of T-cell directed therapy
• Era of biologicals

3
Rheumatoid arthritis

• Chronic inflammatory symmetrical polyarthritis
• Damages joints irreversibly
• 3F1M
• Prevalence 0.5-1
• Rheumatoid factor positive

4
RA aetiology pathogenesis

• Environment
• Proven
• Smoking
• Unproven
• Infection
• Dietary
• Stress
• Autoimmunity RF, anti-CCP
• Genetics
• HLA-DR4
• PTPN22

5
Consequences of RA

• Premature mortality
• Increased morbidity
• Significant impact on quality of life
• Pain with associated functional disability
• Fatigue, 81 of patients 41 with severe fatigue
• Depression
• Work disability
• 25 within 7 years of onset, 50 within 21 years
• 33 reduction in income vs non work-disabled

Wolfe F, Hawley D J, J Rheum. 1998252108-2117. W
olfe F et al. Arthritis Rheum. 199437481-494.
6
Economic Burden in Europe

• In West Germany, RA costs were gtDM 40 billion
  (US 17.6 billion) in 1994 for treatment alone
• In the UK, average RA outpatient cost per case
  per year was 798 (US 1,126) and 1,253 (US
  1,769) per inpatient in 1997
• Rheumatoid arthritis per capita costs average
• 49 of cost of cancer
• 68 of cost of stroke
• 82 of cost of coronary heart disease
• 5 times the cost of motor vehicle accidents

Knorr U. Versicherungsmedizin. 1994.Rothfuss J.
Akt Rheumatol. 1997.Lubeck DP et al. Arthritis
Rheum. 198629488493.Lorig KR et al. Arthritis
Rheum. 199336439446.
7
Indirect Productivity Costs of RA

• Sweden 37 retired early after the first 2
  years of RA
• Finland 64 retired after 8 years
• The Netherlands 60 were not employed
• 73 full disability from RA
• 21 partial disability from RA

8
Synopsis of talk

• What is rheumatoid arthritis
• Pathogenesis synovitis
• Mechanism of bone damage
• CsA as model of T-cell directed therapy
• Era of biologicals

9
The pathogenesis of rheumatoid arthritis
Normal
Rheumatoid Arthritis (RA)
Synovial membrane
Pannus
Inflamed synovial membrane
Cartilage
Capsule
Major cell typeneutrophils
Synovial fluid
Keystone E, et al. Rheum Dis Clin N Am.
199824629- Fox D. Arch Intern Med.
2000160437
10
Pathogenesis
CD4 T helper cells
CD8 T cells
11
TNFa
GM-CSF
IL-1b
IL-17
12
RA- pathogenesis the players

• Macrophages
• T cells
• Synovial fibroblasts
• B cells

13
mf
Inflammation
B cell
Rheumatoid factor
Synovio cyte
Cartilage damage
14
COX-2
Cartilage Bone Damage
osteoclast
15
T cells and target cells

• Interferon g
• Cell-to-cell interction
• RANK-L activates osteoclasts
• IL-17 activates osteoclasts
• activates other target cells

16
RA Pathogenesis mediators

• Macrophages TNFa, IL-1, IL-6, GM-CSF, reactive
  oxygen species, prostaglandins
• B cells RF, anti-citrulline antibodies, other
  auto-antibodies
• Synovial fibroblasts enzymes (collagenases,
  stromelysin)

17
Synopsis of talk

• What is rheumatoid arthritis
• Pathogenesis synovitis
• Mechanism of bone damage
• CsA as model of T-cell directed therapy
• Era of biologicals

18
Pathogenesis bone damage
T cell
Bone
19
Antigenic peptides
Antigen Presenting Cells
Disease specific treatment
CD4 T cells
Activated CD4 T cells
Monocytes/macrophages synoviocytes, B
cells endothelial cells, cytokines,
RF Enzymes, Small molecular weight mediators etc
Non-specific anti-inflammatory treatment
Inflammation
Joint Damage
20
Synopsis of talk

• What is rheumatoid arthritis
• Pathogenesis synovitis
• Mechanism of bone damage
• CsA as model of T-cell directed therapy
• Era of biologicals

21
CsA Mode of action
T Cell

• CsA binds to cyclophillin
• CsA-cyclophillin complex binds to calcineurin,
  blocking calcium activation
• Prevents activation of NF-AT, inhibiting
  transcription

CsA
IL-2
Cyclophillin
Ca Calcineurin
NF-AT
Bentin J. Clin Rheumatol. 199514(suppl 2)22-5
Cyclosporin Prescribing Information. Novartis
Pharmaceuticals Corporation East Hanover, New
Jersey August 2002.
22
CsA Immunological Effects
23
Clinical efficacy of cyclosporin in severe RA
Tugwell P et al (1995) N Eng J Med 333
137-41
24
Cyclosporin slows joint damage
Forre O et al (1994) Arthritis Rheum 37 1506-12
25
Developments from success CsA

• Leflunomide (arava)
• Inhibition T-cell co-stimulation (biologics)

26
Leflunomide Blocks T Cell Clonal Expansion
RestingT Cell
Leflunomide
Activation
G0
G1
S
Fox et al. 1999 Clin Immunol 931.
27
Synopsis of talk

• What is rheumatoid arthritis
• Pathogenesis synovitis
• Mechanism of bone damage
• CsA as model of T-cell directed therapy
• Era of biologicals

28
RA pathogenesis the outcome of clinical trials

• Anti-Cytokines
• Tumour necrosis factor a in the clinic
• Interleukin 1 very weak effect, in the clinic
• Interleukin 6 on trial
• Anti-B cells
• Rituximab in the clinic
• Anti-T cells
• Leflunomide, cyclosporin A
• Abatacept (CTLA4.Ig) in the clinic
• Anti-CD4 under trial

29
STRUCTURE OF ETANERCEPT
P75 extra-cellular domain
IgG1 Fc region
30
Overall responses (25mg twice weekly)
31
Monoclonal Anti-TNF-? Antibodies
32
Infliximab MTX (ATTRACT)ACR Responses at 30
and 54 Weeks
Plt.001
Plt.001
Plt.001
Patients
Plt.001
Plt.001
Plt.001
ACR20
ACR50
ACR70
vs placebo ATTRACT Anti-Tumor Necrosis Factor
Trial in Rheumatoid Arthritis with Concomitant
Therapy.
Maini R, et al. Lancet. 19993541932-9. Lipsky
PE, et al. N Engl J Med. 20003431594-1602.
33
Adalimumab gives sustained improvements in signs
symptoms of RA at 1 year and 3 years
Double-blind period Placebo control
Open-label follow-up
0
Keystone et al. Rheumatol 2004 43 (Suppl 2)
ii10 (oral presentation). Keystone et al.
Radiographic inhibition of structural damage
sustained in patients with long-standing
rheumatoid arthritis following 3 years of
treatment with adalimumab (Humira) plus
methotrexate. Arthritis Rheum 2004 50 (9) S189
34
Adalimumab inhibits radiographic progression at 1
year 3 years
Est. Yearly Progression
40 mg Adalimumab eow MTX
20
20.4
Blinded
Open Label
15
10
6.8
Mean Change from Baseline
5

0.16
0

-0.43
-5
1 year
3 years
61 pts treated with HUMIRA had no change in
total Sharp Score after 3 years
plt0.05 vs placebo (baseline value).
Keystone et al. Rheumatol 2004 43 (Suppl 2)
ii10 (oral presentation). Keystone et al.
Radiographic inhibition of structural damage
sustained in patients with long-standing
rheumatoid arthritis following 3 years of
treatment with adalimumab (Humira) plus
methotrexate. Arthritis Rheum 2004 50 (9) S189
35
RA pathogenesis the outcome of clinical trials

• Anti-Cytokines
• Tumour necrosis factor a in the clinic
• Interleukin 1 very weak effect, in the clinic
• Interleukin 6 on trial
• Anti-B cells
• Rituximab in the clinic
• Anti-T cells
• Leflunomide, cyclosporin A
• Abatacept (CTLA4.Ig) in the clinic
• Anti-CD4 under trial

36
Rituximab Disease Activity Scores
37
Median CD19 (Up to Week 24)
Rituximab
Median CD19 (103/?L)
Time (Days)
38
Mean Total Immunoglobulins (IgG/A/M)
Rituximab
39
Median Changes in RF (Total)
Rituximab
40
What are predictors of rituximab response?

• Not related to fall in Igs
• Not related to fall in RF
• Not related to duration of B-cell depletion
• ? Indirect effect on T-cells?

How does rituximab work?
41
(No Transcript)
42
RA pathogenesis the outcome of clinical trials

• Cytokines
• Tumour necrosis factor a in the clinic
• Interleukin 1 very weak effect
• Interleukin 6 on trial
• B cells
• Rituximab in the clinic
• T cells
• Leflunomide, cyclosporin A
• Abatacept (CTLA4.Ig) in the clinic
• Anti-CD4 under trial

43
2-signals required for T-cell activation
44
CTLA4 and regulation of T-cell activation
45
Structure of Abatecept
46
Mechanism abatacept therapy
47
Clinical efficacy inhibition of T-cell
activation with abatacept
Kremer JL et al (2003) N Eng J Med 349 1907-15
48
RA pathogenesis the outcome of clinical trials

• Cytokines
• Tumour necrosis factor a in the clinic
• Interleukin 1 very weak effect
• Interleukin 6 on trial
• B cells
• Rituximab in the clinic
• T cells
• Leflunomide, cyclosporin A
• Abatacept (CTLA4.Ig) in the clinic
• Anti-CD4 under trial

49
Role of CD4 in costimulation
50
Lymphokines/chemokines produced by RA synovial
membrane T cells

• interleukin 2
• interferon g
• interleukin 6
• IL-8 chemotactic for PMN
• MCP-1 chemotactic for macrophages